JP4394442B2 - Spiro-hydantoin compounds useful as anti-inflammatory agents - Google Patents

Description

Detailed Description of the Invention

(Related application)
This application includes US Provisional Application No. 60 / 326,361 (filed October 1, 2001), US Provisional Application No. 60 / 354,113 (filed February 4, 2002), and US Provisional Application No. 60 / 400,259 ( Claims the benefit of (filed Aug. 1, 2002), which form part of this specification.

(Technical field)
The present invention relates to spiro-hydantoin compounds, pharmaceutical compositions containing the compounds, and methods of using these compounds in treating inflammatory or immune diseases.

(Background technology)
Cells adhere to other cells and substrates by specific and controlled processes that are important for various biological functions. Proper functioning of the immune system depends on adhesive interactions and cell migration. An important event in the immune response involves the migration of leukocytes to the disease site. During the inflammatory response, leukocytes are recruited to the site of injury and are extravasated by cell interactions (including cell-cell and cell-matrix adhesion).

  One family of molecules that perform important adhesion functions are integrins. Integrins are expressed on the cell surface and function in cell-cell and cell-substrate adhesion. Integrins are alpha-beta heterodimers; each integrin has an alpha (α) subunit that binds non-covalently to the beta (β) subunit. When activated, integrins bind to extracellular ligands and adherence (expression of integrins on the cell surface alone is not sufficient for adhesion-they must be activated to adhere) Trigger. The integrin activation state is transient, so that there is a fast flow between attached and non-attached states that are important for cell movement, for example, cells attach quickly to various cell surfaces and matrices. As well as the ability to move between cells and tissues.

CD 11 / CD18 containing integrin subfamilies, four known integrins having a beta ₂ or CD18 subunit, i.e. leukocyte function-associated antigen (Lymphocyte Function-associated Antigen) 1 (LFA-1) (CD11a / CD18 or alpha _L beta _2); macrophage antigen 1 (Mac-1) (CD11b / CD18 or _{α M β 2); p150,95 (} CD11c / CD18 or alpha _x beta _2); and alpha _D beta ₂ is present. The CD11 / CD18 family of integrins are also called leukocyte integrins because they are expressed on the surface of various leukocytes and they mediate numerous inflammation-related cell interactions. See “The Dynamic Regulation of Integrin Adhesiveness” by Diamond et al., Current Biology, Vol. 4 (1994) pp. 506-532.

  Ligands for LFA-1 and Mac-1 include the intercellular adhesion molecule (ICAM) ICAM-1. The major CD11 / CD18 integrin is LFA-1, which also binds to ICAM-2 and ICAM-3. ICAMs are present on endothelial cells, leukocytes, and other cell types, and their interaction with CD11 / CD18 integrins is important for immune system function. Interactions between CD18 integrins (particularly LFA-1) and ICAMs are responsible for antigen presentation, T-cell proliferation, and adhesion between endothelium and activated leukocytes (this is leukocytes from the circulatory system to tissues). Is necessary for the movement of A disease termed “leukocyte adhesion deficiency” is identified in patients with a deficiency in CD18 integrin. These patients are unable to increase a normal inflammatory or immune response; they are, for example, recurrent infections, poor wound healing, granulocytosis, progressive periodontal disease, and umbilical separation Suffer from diseases such as (umbilical cord separation). See Anderson et al., “Leukocyte LFA-1, OKMI, p150, 95 Deficiency Syndrome: Functional and Biosynthesis Studies of Three Kindreds”, Fed. Proc., 44 (1985), 2671-2677.

  Although sufficient levels of DC18 integrins that interact with ICAMs are required to increase the normal immune response, significant cell and tissue damage is associated with chronic inflammatory conditions (inappropriate leukocytes to the disease site). Inflow). Similar to the chronic inflammatory condition, constant replenishment of leukocytes from blood vessels to inflammatory tissues can perpetuate tissue damage and result in excessive fiber repair and autoimmune diseases. Thus, inhibition of the interaction between LFA-1 and / or Mac-1 and their ICAMs may be advantageous for treating inflammatory or immune diseases. For example, blockade of either ICAM or LFA-1 monoclonal antibodies results in the migration of leukocytes into tissues and subsequent development of inflammatory diseases in animal models of rheumatoid arthritis, inflammatory bowel disease and pulmonary inflammation (eg, asthma). Is known to prevent. ICAMs-deficient knockout mice have reduced morbidity to induced arthritis, ischemic injury, impaired pulmonary inflammatory response, and increased tolerance to transplants (eg, heart grafts). See above by Anderson et al. Reports have reported that antibodies that block ICAM-LFA-1 interactions suppress cardiac allograft rejection and islet cell xenograft rejection in animal models. See "The Role of Cell Adhesion Molecules in Immunopathology" by Gorski, Immunology Today, 15 (1994), pages 251-255.

Compounds that inhibit CD18 integrins, ICAMs, and / or LFA-1: ICAM interactions can potentially show a wide range of utility in treating inflammatory or immune diseases. Reports indicate that LFA-1 blockade inhibits leukemia influx in almost any system (including skin, peritoneum, synovium, lung, kidney and heart), and ICAM-1 blockade is similar. It would be expected to have an effect. Also, current therapies for many inflammatory or immune diseases have weaknesses. For example, current treatments for asthma include β ₂ -agonists, inhaled corticosteroids and LTD ₄ antagonists. However, β ₂ -agonists have limited efficacy, and inhaled corticosteroids present safety issues. To treat psoriasis, current therapies include PUVA, methotrexate, cyclosporine A and topical treatment. The first three of these therapies create toxicity problems with long-term use (6-9 months), while topical treatment has limited efficacy. In addition, these treatments are typically applied only in response to flare and not as a preventive treatment.

According to reports, thiadiazole-based compounds (International Publication No. WO 99 / 20,618, “Thiadiazole Amides Useful as Anti-Inflammatory Agents”) are compounds that inhibit LFA-1 / ICAM for use as anti-inflammatory drugs. (According to Pharmacia & Upjohn Co.); and WO 99 / 20,617 (According to Pharmacia and Upjohn); -1 Mediated Cell Adhesion ”, J. Med. Chem. 38 (1995) pages 1057-1059). According to reports, small molecules that are antagonists to the binding of ICAMs to CD18 integrin include: Various benzylamine and 2-bromobenzoyltryptophan compounds (International Publication No. WO99 / 49,856, “Antagonists for Treatment of CD11 / CD18 Adhesion Receptor Mediated Disord ers (filed by Genentech, Inc.), as well as 1- (3,5-dichlorophenyl) imidazolidine (International Publication No. WO 98/39303, “Small Molecules Useful in the Treatment of Inflammatory Disease” (Boehringer Ingelheim Pharmaceuticals, (See also application by Inc.): Boehringer patent applications WO 01/07052, WO 01/07048, WO 01/07044, WO 01/06984 and WO 01/07440). 00/59880, WO 00/39081, WO 02/02522, WO 02/02539 (all filed by Abbott Laboratories) LFA-1 antagonist compounds are also disclosed in WO 02/059114 (by Genentech), WO 02/42294 (by Celltech), WO 01/51508 (by Science and Technology corporation), WO 00/21920 and WO 01/58853 (both by Hoffmann-LaRoche), WO 99/11258, WO 00/48989 and WO 02 / 28832 (all by Novartis). Hydantoin compounds are disclosed in International Publication No. WO 01/30781 A2 (published on May 3, 2001)) (“Inhibitors of α _L β ₂ Mediated Cell Adhesion” by Tanabe Seiyaku Co. Ltd) and International Publication No. WO 02/44181 ( Published on June 6, 2002) "Hydantoin Compounds Useful as Anti-Inflammatory Agents" (by the assignee and with a common inventor).

  As can be appreciated, those skilled in the field of pharmaceutical research have continued to develop new compounds and compositions (eg, inhibitors of leukocyte integrins and / or ICAMs) to treat inflammatory or immune diseases. Yes. Particularly in the field of immune responses, many individuals respond differently to different drugs. Accordingly, there is an interest in providing different structures or mechanisms of action to give consumers choice as well as pharmaceutical compositions that exhibit increased efficacy and reduced side effects. The present invention relates to aryl or heteroaryl substituted spirohydantoin compounds that are effective as antagonists of leukocyte integrins and / or ICAMs. Diazaspiroheptane compounds are described in Park et al., `` Preparation of a 990 Member Chemical Compound Library of Hydantoin and Isoxazoline-Containing Heterocycles Using Multipin Technology '', J. Comb. Chem., 3 (2) (2001), 171-76. Page. Spiroheterocycles are also described by Couture et al., “Chemistry of Cyclic aminooxycarbenes”, Can. J. Chem. 75 (9) (1997) 1281-1294; Brandstetter et al., “Glucofuranose Analogs of Hydanocidin”, Tetrahedron, 52 (32). Volume (1996), pages 10721-10736; “Spirohydantois of Glucofuranose: Analogs of Hydantocidin” by Brandstetter et al., Tetrahedron Lett. 36 (12) (1995) pages 2149-52; US Pat. Nos. 6,022,875, 4,241,208, 4,066,615 and 3,941,744; and International Patent Application No. WO 01/45704. WO 01/94346 discloses 1,3,8-triaza-spiro-4,5-decan-4-one derivatives as neurokinin receptor antagonists.

  Each of the patents, patent applications and publications cited above and below form part of the present specification.

で示す化合物、そのエナンチオマーおよびジアステレオマー、並びにそれらの医薬的に許容し得る塩、水和物、溶媒和物およびそのプロドラッグを提供する。
上記式中、
ＬおよびＫは独立して、ＯまたはＳであり；
Ｚは、ＮまたはＣＲ_４ｂであり；
Ａｒは、アリールまたはヘテロアリールであり；
Ｇは、ＴまたはＭの位置で環Ａと結合し、そして
（ｉ）環Ａの炭素原子と結合する場合には、Ｇは、結合、−Ｏ−、−Ｎ−、−Ｓ−、Ｃ_１〜４アルキレン、Ｃ_１〜４置換アルキレン、または二価のアルコキシ、アルキルチオ、アミノアルキル、スルホニル、スルホンアミジル、アシルまたはアルコキシカルボニルから選ばれるか；あるいは、
（ｉｉ）環Ａの窒素原子と結合する場合には、Ｇは、結合、Ｃ_１〜４アルキレン、Ｃ_１〜４置換アルキレン、二価のアシルもしくはアルコキシカルボニル、または二価のアルコキシ、アルキルチオ、アミノアルキル、スルホニルもしくはスルホンアミジルから選ばれ、そして（ｉｉ）の場合には、各該Ｇ基は環Ａと直結する炭素を少なくとも１つ有し；
Ｊは、−Ｏ−、−Ｓ−、−ＮＲ_３−、−Ｎ＝、−Ｓ(＝Ｏ)−、−ＳＯ_２−、−ＮＨＳＯ_２−、置換もしくは無置換のＣ_１〜３アルキレン、置換もしくは無置換のＣ_２〜３アルケニレン、無置換のＣ_１〜２ヘテロアルキレン、ヘテロアルキレン直鎖内に１〜２個の炭素原子を有する置換ヘテロアルキレンであるか、あるいは、
Ｊは、存在せず、その結果環Ａは３員環であり；
Ｔは、Ｇ−ＡｒがＴと結合する場合にはＴ_１であり；そして、Ｇ−ＡｒがＭと結合する場合には、Ｔ_２であり；
Ｍは、Ｇ−ＡｒがＭと結合する場合にはＭ_１であり；そして、Ｇ−ＡｒがＴと結合する場合には、Ｍ_２であり；
Ｔ_１およびＭ_１は、−Ｎ−および−Ｃ(Ｒ_５)−から選ばれ；
Ｊ、ＭおよびＴが３〜６員の飽和または部分的に不飽和のシクロアルキルまたは１〜４個のヘテロ原子を有するヘテロ環（ここで、該ヘテロ環Ａの２個の隣接するヘテロ原子が、同時に−Ｏ−または−Ｓ−から選ばれることはない）を定義するように選ばれるという条件で、Ｔ_２およびＭ_２は、−Ｏ−、−Ｓ−、−Ｎ(Ｒ_６)−、−Ｎ＝、−Ｓ(＝Ｏ)−、−ＳＯ_２−、−ＮＨＳＯ_２−、または−Ｃ(Ｒ_７Ｒ_８)−から選ばれ；
Ｒ_２は、水素原子、アルキル、置換アルキル、ＯＲ_１２、ＮＲ_１２Ｒ_１３、Ｃ(＝Ｏ)Ｒ_１２、ＣＯ_２Ｒ_１２、Ｃ(＝Ｏ)ＮＲ_１２Ｒ_１３、ＮＲ_１２Ｃ(＝Ｏ)Ｒ_１３、ＮＲ_１２Ｃ(＝Ｏ)ＯＲ_１３、Ｓ(Ｏ)_ｐＲ_１３ａ、ＮＲ_１２ＳＯ_２Ｒ_１３ａ、ＳＯ_２ＮＲ_１２Ｒ_１３、シクロアルキル、ヘテロシクロ、アリールまたはヘテロアリールから選ばれ；
Ｒ_４ａ、Ｒ_４ｂおよびＲ_４ｃは独立して、水素、ハロゲン、アルキル、置換アルキル、アルケニル、置換アルケニル、ニトロ、シアノ、ＳＲ_１４、ＯＲ_１４、ＮＲ_１４Ｒ_１５、ＮＲ_１４Ｃ(＝Ｏ)Ｒ_１５、ＣＯ_２Ｒ_１４、Ｃ(＝Ｏ)Ｒ_１４、−Ｃ(＝Ｏ)ＮＲ_１４Ｒ_１５、アリール、ヘテロシクロ、シクロアルキル、またはヘテロアリールから選ばれ；
Ｒ_３およびＲ_６は独立して、水素、アルキル、置換アルキル、ヒドロキシ、アルコキシ、アルケニル、置換アルケニル、アミノアルキル、アルキルチオ、Ｃ(＝Ｏ)Ｈ、アシル、アミド、アルコキシカルボニル、スルホニル、スルホンアミジル、シクロアルキル、ヘテロシクロ、アリール、またはヘテロアリールから選ばれ；
Ｒ_５、Ｒ_７およびＲ_８は、
（ｉ）独立して、水素、アルキル、置換アルキル、ハロゲン、ニトロ、シアノ、ヒドロキシ、アルコキシ、アルケニル、置換アルケニル、アミノアルキル、アルキルチオ、Ｃ(＝Ｏ)Ｈ、アシル、ＣＯ_２Ｈ、アミド、アルコキシカルボニル、スルホニル、スルホンアミジル、シクロアルキル、ヘテロシクロ、アリール、またはヘテロアリールから選ばれるか、
（ｉｉ）Ｒ_７およびＲ_８が一緒になって、シクロアルキル、ヘテロ環、または酸素原子への二重結合（ケト(＝Ｏ)基と定義する）を形成し得るか、あるいは、
（ｉｉｉ）Ｒ_５またはＲ_８の一方が、それぞれＴとＭの間またはＭとＪの間に二重結合が存在するように結合であり得て、その結果環Ａは部分的に不飽和であり；
Ｒ_１２、Ｒ_１３、Ｒ_１４およびＲ_１５は、
（ｉ）各々独立して、水素、アルキル、置換アルキル、シクロアルキル、アリール、ヘテロアリール、またはヘテロシクロから選ばれるか、あるいは、
（ｉｉ）Ｒ_１２がＲ_１３と一緒になっておよび／またはＲ_１４がＲ_１５と一緒になって、ヘテロアリール、またはヘテロ環を形成し；
Ｒ_１３ａは、アルキル、置換アルキル、シクロアルキル、アリール、ヘテロアリール、またはヘテロシクロから選ばれ；そして、
ｐは、１または２である。 (Summary of Invention)
The present invention provides a compound of formula (I) useful for treating inflammatory or immune diseases:

And the enantiomers and diastereomers thereof, and their pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof.
In the above formula,
L and K are independently O or S;
Z is N or CR _4b ;
Ar is aryl or heteroaryl;
G is bonded to ring A at the T or M position, and (i) when bonded to a carbon atom of ring A, G is a bond, —O—, —N—, —S—, C _1. Selected from _˜4 alkylene, C _1-4 substituted alkylene, or divalent alkoxy, alkylthio, aminoalkyl, sulfonyl, sulfonamidyl, acyl or alkoxycarbonyl;
(Ii) when bound to the nitrogen atom of ring A, G is a bond, C _1-4 alkylene, C _1-4 substituted alkylene, divalent acyl or alkoxycarbonyl, or divalent alkoxy, alkylthio, amino Selected from alkyl, sulfonyl or sulfonamidyl, and in case (ii) each G group has at least one carbon directly attached to ring A;
J is —O—, —S—, —NR ₃ —, —N═, —S (═O) —, —SO ₂ —, —NHSO ₂ —, substituted or unsubstituted C _1-3 alkylene, substituted Or unsubstituted C _2-3 alkenylene, unsubstituted C _1-2 heteroalkylene, substituted heteroalkylene having 1-2 carbon atoms in the heteroalkylene straight chain, or
J is absent, so that ring A is a 3-membered ring;
T is T ₁ when G-Ar is bound to T; and T is G ₂ when G-Ar is bound to M;
M is M ₁ when G-Ar binds M; and M ₂ when G-Ar binds T;
T ₁ and M ₁ are selected from —N— and —C (R ₅ ) —;
J, M and T are 3 to 6 membered saturated or partially unsaturated cycloalkyl or heterocycle having 1 to 4 heteroatoms, wherein the two adjacent heteroatoms of the heterocycle A are T ₂ and M ₂ are —O—, —S—, —N (R ₆ ) —, provided that they are selected to define Selected from —N═, —S (═O) —, —SO ₂ —, —NHSO ₂ —, or —C (R ₇ R ₈ ) —;
R ₂ is a hydrogen atom, alkyl, substituted alkyl, OR ₁₂ , NR ₁₂ R ₁₃ , C (═O) R ₁₂ , CO ₂ R ₁₂ , C (═O) NR ₁₂ R ₁₃ , NR ₁₂ C (═O) R ₁₃ , NR ₁₂ C (═O) OR ₁₃ , S (O) _p R _13a , NR ₁₂ SO ₂ R _13a , SO ₂ NR ₁₂ R ₁₃ , cycloalkyl, heterocyclo, aryl or heteroaryl;
R _4a , R _4b and R _4c are independently hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, nitro, cyano, SR ₁₄ , OR ₁₄ , NR ₁₄ R ₁₅ , NR ₁₄ C (═O) R ₁₅ , CO ₂ R ₁₄ , C (═O) R ₁₄ , —C (═O) NR ₁₄ R ₁₅ , aryl, heterocyclo, cycloalkyl, or heteroaryl;
R ₃ and R ₆ are independently hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, alkenyl, substituted alkenyl, aminoalkyl, alkylthio, C (═O) H, acyl, amide, alkoxycarbonyl, sulfonyl, sulfonamidyl , Cycloalkyl, heterocyclo, aryl, or heteroaryl;
R ₅ , R ₇ and R ₈ are
(I) Independently, hydrogen, alkyl, substituted alkyl, halogen, nitro, cyano, hydroxy, alkoxy, alkenyl, substituted alkenyl, aminoalkyl, alkylthio, C (═O) H, acyl, CO ₂ H, amide, alkoxy Selected from carbonyl, sulfonyl, sulfonamidyl, cycloalkyl, heterocyclo, aryl, or heteroaryl,
(Ii) R ₇ and R ₈ can be taken together to form a double bond to a cycloalkyl, heterocycle, or oxygen atom (defined as a keto (═O) group), or
(Iii) one of R ₅ or R ₈ can be a bond such that there is a double bond between T and M or M and J, respectively, so that ring A is partially unsaturated. Yes;
R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are
(I) each independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo, or
(Ii) R ₁₂ is taken together with R ₁₃ and / or R ₁₄ is taken together with R ₁₅ to form a heteroaryl, or heterocycle;
R _13a is selected from alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo; and
p is 1 or 2.

  The present invention relates to a medicament useful for treating an immune or inflammatory disease comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent. It also relates to a composition. The invention further relates to a method of treating an immune or inflammatory disease, the method comprising administering to a patient in need of said treatment a therapeutically useful amount of a compound of formula (I).

(Detailed description of the invention)
The definitions of terms used in the present specification and claims are shown below. The initial definition given for a group or term in this application applies to that group or term in this specification and in the claims individually or as part of another group, unless otherwise specified.

The term “alkyl” means a straight or branched hydrocarbon group having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. A lower alkyl group, that is, an alkyl group having 1 to 4 carbon atoms is most preferable. When a number is shown as a subscript after the symbol “C”, the subscript more specifically defines the number of carbon atoms that a group may contain. For example, “C _1-6 alkyl” means a linear or branched alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n -Pentyl etc.). The subscript “0” means a bond. Accordingly, the term hydroxy C _0-2 alkyl or (C _0-2 ) hydroxyalkyl includes hydroxy, hydroxymethyl and hydroxyethyl.

The term “substituted alkyl” means an alkyl group as defined above having 1, 2 or 3 substituents. The substituent is halo (eg, trifluoromethyl), alkenyl, substituted alkenyl, alkynyl, nitro, cyano, oxo (═O), OR _a , SR _a , (═S), —NR _a R _b , —N (Alkyl) ₃ ⁺ , —NR _a SO ₂ , —NR _a SO ₂ R _c , —SO ₂ R _c , —SO ₂ NR _a R _b , —SO ₂ NR _a C (═O) R _b , SO ₃ H , —PO (OH) ₂ , —C (═O) R _a , —CO ₂ R _a , —C (═O) NR _a R _b , —C (═O) (C _1-4 alkylene) NR _a R _{b, -C (= O) NR} a (SO 2) R b, -CO 2 (C 1~4 _{alkylene) NR a R b, -NR a} C (= O) R b, -NR a CO 2 R b , -NR _{a (C 1 to 4 alkylene) CO 2 R b, = N} -OH, = N-O- alkyl, aryl, cycloalkyl, heterocyclo Contact Selected from the group consisting of beauty / or heteroaryl, wherein _{R a} and _{R b} are hydrogen, alkyl, _alkenyl, CO _{2 H,} CO 2 _{(alkyl), C 3 to 7} cycloalkyl, phenyl, benzyl, phenylethyl , Naphthyl or 4-7 membered heterocyclo, or 5-6 membered heteroaryl, or can be combined with the same nitrogen atom to form a heterocyclo or heteroaryl, and R _c is R _a and R Selected from the same group as _b , but not hydrogen. Each of R _a and R _{b in} the case other than hydrogen, and each R _c is optionally 1 to 3 bonded on any available carbon or nitrogen atom of R _a , R _b and / or Rc. Wherein the substituent is (C _1-6 ) alkyl, (C _2-6 ) alkenyl, hydroxy, halogen, cyano, nitro, CF ₃ , O (C _1-6 alkyl), OCF ₃ , C (═O) H, C (═O) (C _1-6 alkyl), CO ₂ H, CO ₂ (C _1-6 alkyl), NHCO ₂ (C _1-6 alkyl), —S ( C _1-6 alkyl), —NH ₂ , NH (C _1-6 alkyl), N (C _1-6 alkyl) ₂ , N (CH ₃ ) ₃ ⁺ , SO ₂ (C _1-6 alkyl), C ( ═O) (C _1-4 alkylene) NH ₂ , C (═O) (C _1-4 alkylene) NH (alkyl), C (═O) (C _1-4 alkylene) N ( C _1-4 alkyl) ₂ , C _3-7 cycloalkyl, selected from the group consisting of phenyl, benzyl, phenylethyl, phenyloxy, benzyloxy, naphthyl, 4-7 membered heterocyclo, or 5-6 membered heteroaryl It is. When a substituted alkyl is substituted with an aryl, heterocyclo, cycloalkyl, or heteroaryl group, the ring system is as defined below and thus itself is 0, 1, 2, or 3 substituents (this Can also be defined below).

を意味することを意図すると、理解するであろう。 Those skilled in the art, when the symbol “CO ₂ ” is used in this application, refers to the group:

Will be understood as intended.

When the term “alkyl” is used with another group (eg, “arylalkyl”), the combination more specifically defines at least one of the substituents that the substituted alkyl comprises. For example, “arylalkyl” means a substituted alkyl group as defined above when at least one of the substituents is aryl (eg, benzyl). Thus, the term: aryl (C _0-4 ) alkyl includes substituted lower alkyl having at least one aryl substituent, and this also includes aryl directly attached to another group (ie, aryl (C ₀ )). Alkyl).

  The term “alkenyl” refers to a straight or branched chain hydrocarbon group having 2 to 12 carbon atoms and at least one double bond. Most preferred is an alkenyl group having 2 to 6 carbon atoms having one double bond.

  The term “alkynyl” refers to a straight or branched chain hydrocarbon group having 2 to 12 carbon atoms and at least one triple bond. An alkynyl group having 2 to 6 carbon atoms having one triple bond is most preferable.

The term “alkylene” refers to a divalent linear or branched hydrocarbon group having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms (eg, {—CH ₂ —} _n (Wherein n is 1 to 12, preferably 1 to 8.) A lower alkylene group, that is, an alkylene group having 1 to 4 carbon atoms, is most preferred. “Alkynylene” means a divalent group of an alkenyl group and an alkynyl group as defined above.

  When referring to substituted alkenyl, alkynyl, alkylene, alkenylene or alkynylene groups, these groups are substituted with one to three of the substituents defined above for substituted alkyl groups.

The term “heteroalkylene” as used in this application refers to saturated and unsaturated divalent straight or branched hydrocarbons having 2 to 12 carbon atoms, preferably 2 to 8 carbon atoms. Means a group, wherein one or two carbons in the straight chain are from —O—, —S—, —S (═O) —, —SO ₂ —, —NH—, or —NHSO ₂ —. It is replaced by the heteroatom chosen. The term “heteroalkylene” includes divalent alkoxy, thioalkyl and aminoalkyl groups as defined below, as well as alkylene and alkenylene groups having combinations of heteroatoms within the alkyl group. As illustrated, “heteroalkylene” in the present application refers to, for example, —S— (CH ₂ ) _1-5 NH—CH ₂ —, —O— (CH ₂ ) _1-5 S (═O) —CH ₂ —. , -NHSO ₂ -CH _{2 -,} - may include CH 2 -NH- groups, such as. The heteroalkylene group preferably does not have two adjacent atoms selected simultaneously from —O— or —S—. Subscript is the term: when used for heteroalkylene (eg, C _2-3 heteroalkylene), the subscript means the number of carbon atoms in the group, plus heteroatoms. Thus, for example, _{C 1 to 2} heteroalkylene, for example _{-NH-CH 2 -, - CH} 2 -NH-CH 2 -, - CH 2 -CH 2 -NH -, - S-CH 2 -, - CH 2 - _{S-CH 2 -, - O} -CH 2 -NH-CH 2 -, may include groups such as CH ₂ -O-CH 2.

The term “substituted heteroalkylene” means a heteroalkylene group, as defined above, wherein at least one of the nitrogen or carbon atoms in the heteroalkylene chain is bonded to (or substituted with) a group other than hydrogen. The carbon atoms in the heteroalkylene chain can be substituted with a group selected from the substituents set forth above for substituted alkyl groups, or with additional alkyl groups or substituted alkyl groups. The nitrogen atom of the heteroalkylene chain can be substituted with a group selected from alkyl, alkenyl, alkynyl, cyano or A ₁ -QA ₂ -R _h . Where A ₁ is a bond, C _1-2 alkylene or C _2-3 alkenylene; Q is a bond, —C (═O) —, —C (═O) NR _d —, —C (═S) NR _d- , -SO _2- , -SO ₂ NR _d- , -CO ₂ -or -NR _d CO _2- ; A ₂ is a bond, C _1-3 alkylene, C _2-3 alkenylene, -C _{1 -4} alkylene _-NR d _-, - _C 1~4 alkylene _{-NR d C (= O) -} , - C 1~4 alkylene -S _-, - _C 1~4 alkylene -SO ₂ -, or _{-C. 1 to 4} alkylene -O-; wherein said a ₂ alkylene groups are branched or straight chain, be substituted in the same manner as defined herein for substituted alkylene optionally the thing; R _h is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, And R _d is selected from hydrogen, alkyl as defined herein, or substituted alkyl; however, for substituted heteroalkylene Rh, A ₁ , Q, and A ₂ are When each is a bond, R _h is not hydrogen. When R _h is aryl, heteroaryl, cycloalkyl or heterocyclo, the rings are optionally substituted with 1 to 3 groups as defined below within the definitions for these terms.

The term “alkoxy” means an alkyl or substituted alkyl group as defined above having 1 or 2 oxygen atoms (—O—) in the alkyl chain. For example, the term “alkoxy” refers to the group: —O—C _1-12 alkyl, — (C _1-6 alkylene) —O—C _1-6 alkyl, — (C _1-4 alkylene-O—C _1- etc. ₄ alkylene) _{-O-C 1 to 4} alkyl.

The term “thioalkyl” or “alkylthio” means an alkyl or substituted alkyl group, as defined, having 1 or 2 sulfur atoms in the alkyl chain. For example, the term “thioalkyl” or “alkylthio” includes the groups: —S—C _1-12 alkyl, — (S—C _1-6 alkylene) —S—C _1-6 alkyl, and the like.

The term “aminoalkyl” or “alkylamino” means an alkyl or substituted alkyl group as defined above having one or two nitrogen (—NR—) atoms in the alkyl chain. For example, the term “aminoalkyl” refers to the group: —NR—C _1-12 alkyl, —NR—C _1-6 alkylene-NR—C _1-6 alkyl (where R is preferably hydrogen, Meaning alkyl or substituted alkyl as defined) and the like. When a subscript is used for alkoxy, thioalkyl or aminoalkyl, the subscript means the number of carbon atoms that the group may contain, as well as the number of heteroatoms. Thus, for example, a monovalent C _1-2 aminoalkyl is a group: —CH ₂ —NH ₂ , —NH—CH ₃ , — (CH ₂ ) ₂ —NH ₂ , —NH—CH ₂ —CH ₃ , — CH ₂ -NH ₂ -CH ₃ and -N- (CH ₃₎ containing _2. Lower aminoalkyl includes aminoalkyl having 1 to 4 carbons. “Amino” means the group NH ₂ .

The alkoxy, thioalkyl or aminoalkyl group can be monovalent or divalent. For “monovalent” it means that the group has one valence (ie the ability to bind to another group) and for “divalent” it means that the group has two valences. It means having. Thus, for example, monovalent alkoxy is, for example, —O—C _1-12 alkyl, —C _1-6 alkylene-O—C _1-6 alkyl, —C _1-4 alkylene-O—C _1-4 alkylene-O. -C _{1 to 4} includes groups such as alkyl, whereas a bivalent alkoxy is, for example _{-O-C 1 to 12} alkylene -, _{- C 1 to 6} alkylene _{-O-C 1 to 6} alkylene -, - _{C 1 ~ 4} alkylene _{-O-C 1 to 4} alkylene _{-C 1 to 4} alkylene - it includes groups such as.

It should be understood that selection in alkoxy, thioalkyl, and aminoalkyl will be made by those skilled in the art to provide stable compounds. Thus, for example, in the compound of formula (I), when G is bonded to the nitrogen atom (N ^* ) of ring A and is selected from an alkoxy group or alkylthio group, the alkoxy group and alkylthio group are ring A ( At least one carbon directly attached (at the N ^* position) and at least one oxygen atom or sulfur atom away from the nitrogen atom.

The term “acyl” refers to a carbonyl group attached to an organic group, more specifically a group: C (═O) R _e group, and a divalent group: —C (═O) — or —C (═O). R _e- , which is bound to an organic group or ring A in the compound of formula (I). The group R _e is from alkyl, alkenyl, alkynyl, aminoalkyl, substituted alkyl, substituted alkenyl or substituted alkynyl as defined herein, or, where appropriate, the corresponding divalent group (eg, alkylene, alkenylene, etc.). Can be chosen. Thus, in a compound of formula (I), when G indicates that it can be “acyl”, this means that G is —C (═O) and also the group: —C (═O) R _e — or —R _e C (═O) —, where the group R _e is selected from divalent groups (eg, alkylene, alkenylene, alkynylene, divalent aminoalkyl, substituted alkylene, substituted alkenylene, or substituted alkynylene). Intended to encompass the choice of

、並びに式（Ｉ）の化合物における有機基と結合する二価の基：−ＣＯ_２、−ＣＯ_２Ｒｅ−（式中、Ｒ_ｅはアシルについて上で定義する通りである）を意味する。カルボキシ基が結合する有機基は、一価（例えば、−ＣＯ_２−アルキルまたは−ＯＣ(＝Ｏ)アルキル）、二価（例えば、−ＣＯ_２−アルキレン、−ＯＣ(＝Ｏ)アルキレンなど）であり得る。従って、式（Ｉ）の化合物において、Ｇは「アルコキシカルボニル」であり得ると示す場合には、これはＧが−ＣＯ_２、およびまた基：−ＣＯ_２Ｒ_ｅ−または−ＲｅＣＯ_２−（ここでこの場合に、該基：Ｒ_ｅは二価の基（例えば、アルキレン、アルケニレン、アルキニレン、二価のアミノアルキル、置換アルキレン、置換アルケニレンまたは置換アルキニレン）から選ばれる）であるという選択を包含することを意図する。 The term “alkoxycarbonyl” refers to a carboxy group bonded to an organic group (CO ₂ R _e ).

And wherein the divalent radical is bonded with organic groups in the compounds of _(I): -CO _2, (wherein, _{R e} is as defined above for acyl) -CO 2 Re- means. The organic group to which the carboxy group is bonded is monovalent (eg, —CO ₂ -alkyl or —OC (═O) alkyl), divalent (eg, —CO ₂ -alkylene, —OC (═O) alkylene, etc.). possible. Thus, in the compounds of formula (I), when G indicates that it may be “alkoxycarbonyl”, this is because G is —CO ₂ and also the group: —CO ₂ R _e — or —ReCO ₂ — (here In which case the group: R _e is selected from divalent groups (eg selected from alkylene, alkenylene, alkynylene, divalent aminoalkyl, substituted alkylene, substituted alkenylene or substituted alkynylene). I intend to.

The term “amido” or “amidyl” refers to the group C (═O) NR _a R _b , where R _a and R _b are as defined above in the definition for substituted alkyl groups. ).

The term “sulfonyl” refers to a sulfoxide group bonded to an organic group in a compound of formula (I), more specifically a monovalent group: S (O) _1-2- R _e , or a compound of formula (I) A divalent group bonded to an organic group in the compound means -S (O) _1-2 . Thus, in a compound of formula (I), when G indicates that it may be “sulfonyl”, this means that G is —S (═O) or —SO ₂ — and the group: —S (═O) R _e —, —R _e S (═O) —, —SO ₂ R _e — or —R _e SO ₂ — (in this case, the group: R _e is selected from the groups shown above for the acyl group and the alkoxycarbonyl group. Intended to encompass the choice of

The term “sulfonamidyl” means —S (O) ₂ NR _a R _b , where R _a and R _b are as defined above for substituted alkyl groups. In addition, the sulfonamidyl group can be divalent when one of the groups: R _a and R _b is a bond. Thus, in the compounds of formula (I), when it is stated that G may be sulfonamidyl, it is intended to mean that G is a group: —S (O) ₂ NR _a —.

The term “cycloalkyl” means a fully saturated or partially unsaturated hydrocarbon ring having 3 to 9, preferably 3 to 7 carbon atoms. The term “cycloalkyl” includes rings having 0, 1, 2, or 3 substituents. The substituent is halogen, trifluoromethyl, trifluoromethoxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, nitro, cyano, oxo (═O), OR _a , SR _a , (═S), —NR _a R _b, -N ^{_{(alkyl) 3 +, -NR a SO 2}} , -NR a SO 2 R c, -SO 2 R c, -SO 2 NR a R b, -SO 2 NR a C (= O) _{R b, SO 3 H, -PO} (OH) 2, -C (= O) R a, -CO 2 R a, -C (= O) NR a R b, -C (= O) (C 1~ ₄ alkylene) NR _a R _b , —C (═O) NR _a (SO ₂ ) R _b , —CO ₂ (C _1-4 alkylene) NR _a R _b , —NR _a C (═O) R _b , — _{NR a CO 2 R b, -NR} a (C 1~4 _{alkylene) CO 2 R b, = N} -OH, = N-O- alkyl, Reels, selected from cycloalkyl, heterocyclo, and / or heteroaryl, wherein, R _a, R _b, and R _c are as defined above for substituted alkyl groups, and these are also optionally substituted alkyl group Is substituted similarly as shown above in the definition for. The term “cycloalkyl” also has a fused second ring (including, for example, a benzo, heterocyclo, or heteroaryl ring), or a carbon-carbon bridge having 3 to 4 carbon atoms. Is also included. If the cycloalkyl is substituted with an additional ring (or has a fused second ring), the ring optionally has 1-2 (C _1-4 ) alkyl, (C _2-4 ) Alkenyl, halogen, hydroxy, cyano, nitro, CF ₃ , O (C _1-4 alkyl), OCF ₃ , C (═O) H, C (═O) (C _1-4 alkyl), CO ₂ H, CO _{2 (C 1 to 4 alkyl),} NHCO _{2 (C 1~4 alkyl),} - S _(C 1~4 _{alkyl), - NH 2, NH (} C 1~4 alkyl), N _{(C 1 to 4} alkyl) ₂ , N (C _1-4 alkyl) ₃ ⁺ , SO ₂ (C _1-4 alkyl), C (═O) (C _1-4 alkylene) NH ₂ , C (═O) (C _1-4 alkylene) Substituted with NH (alkyl) and / or C (═O) (C _1-4 alkylene) N (C _1-4 alkyl) ₂ .

などを含み、これらのものは場合により該環のいずれかの利用可能な原子上で置換され得る。好ましいシクロアルキル基は、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、

を含む。 Accordingly, in the compound of formula (I), the term “cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, as well as the following ring systems:

These may optionally be substituted on any available atom of the ring. Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

including.

  The term “halo” or “halogen” refers to chloro, bromo, fluoro and iodo.

  The term “haloalkyl” refers to a substituted alkyl having one or more halo substituents. For example, “haloalkyl” includes mono, di, and tri-fluoromethyl.

The term “haloalkoxy” refers to an alkoxy group having one or more halo substituents. For example, “haloalkoxy” includes OCF ₃ .

The term “aryl” means phenyl, biphenyl, 1-naphthyl and 2-naphthyl. The term “aryl” includes rings having 0, 1, 2, or 3 substituents. The substituent is halogen, trifluoromethyl, trifluoromethoxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, nitro, cyano, OR _a , SR _a , (═S), —NR _a R _b , —N (Alkyl) ₃ ⁺ , —NR _a SO ₂ , —NR _a SO ₂ R _c , —SO ₂ R _c , —SO ₂ NR _a R _b , —SO ₂ NR _a C (═O) R _b , SO ₃ H , —PO (OH) ₂ , —C (═O) R _a , —CO ₂ R _a , —C (═O) NR _a R _b , —C (═O) (C _1-4 alkylene) NR _a R _{b, -C (= O) NR} a (SO 2) R b, -CO 2 (C 1~4 _{alkylene) NR a R b, -NR a} C (= O) R b, -NR a CO 2 R b , —NR _a (C _1-4 alkylene) CO ₂ R _b , aryl, cycloalkyl, heterocyclo and / or Or selected from the group consisting of heteroaryl, wherein R _a , R _b and R _c are as defined above for substituted alkyl groups, and these are also optionally substituted as indicated above Is done. In addition, two substituents attached to an aryl, particularly a phenyl group, can be taken together to form a fused or spiro ring (eg, cyclopentyl or cyclohexyl, or fused heterocyclo or heteroaryl). Where aryl is substituted with a further ring (or has a fused second ring), the ring optionally has 1-2 (C _1-4 ) alkyl, (C _2-4 ) Alkenyl, halogen, hydroxy, cyano, nitro, CF ₃ , O (C _1-4 alkyl), OCF ₃ , C (═O) H, C (═O) (C _1-4 alkyl), CO ₂ H, CO _{2 (C 1 to 4 alkyl),} NHCO _{2 (C 1~4 alkyl),} - S _(C 1~4 _{alkyl), - NH 2, NH (} C 1~4 alkyl), N _{(C 1 to 4} alkyl) ₂ , N (C _1-4 alkyl) ₃ ⁺ , SO ₂ (C _1-4 alkyl), C (═O) (C _1-4 alkylene) NH ₂ , C (═O) (C _1-4 alkylene) Substituted with NH (alkyl) and / or C (═O) (C _1-4 alkylene) N (C _1-4 alkyl) ₂ .

などを含み、これらは場合によりいずれかの利用可能な炭素原子または窒素原子上で置換され得る。好ましいアリール基は、場合により置換されたフェニルである。 Thus, an aryl group is for example

These may optionally be substituted on any available carbon or nitrogen atom. A preferred aryl group is optionally substituted phenyl.

The term “heterocyclo” or “heterocycle” refers to substituted and unsubstituted non-aromatic 3-7 membered monocyclic groups, 7-11 membered bicyclic groups, and 10-15 membered tricyclic groups. And means a group in which at least one of the rings has at least one heteroatom (O, S or N). Each ring of a heterocyclo group containing a heteroatom has 1 or 2 oxygen atoms or sulfur provided that the total number of heteroatoms in each ring is 4 or less and the ring further comprises at least one carbon atom. It may contain atoms and / or 1 to 4 nitrogen atoms. The fused rings completing the bicyclic and tricyclic groups can contain only carbon atoms and can be saturated, partially saturated or unsaturated. The nitrogen and sulfur atoms can optionally be oxygenated and the nitrogen atoms can optionally be quaternized. The heterocyclo group can be attached on any available nitrogen or carbon atom. The heterocycle may contain 0, 1, 2 or 3 substituents. The substituent is halogen, trifluoromethyl, trifluoromethoxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, nitro, cyano, oxo (═O), OR _a , SR _a , (═S), —NR _a R _b, -N ^{_{(alkyl) 3 +, -NR a SO 2}} , -NR a SO 2 R c, -SO 2 R c, -SO 2 NR a R b, -SO 2 NR a C (= O) _{R b, SO 3 H, -PO} (OH) 2, -C (= O) R a, -CO 2 R a, -C (= O) NR a R b, -C (= O) (C 1~ ₄ alkylene) NR _a R _b , —C (═O) NR _a (SO ₂ ) R _b , —CO ₂ (C _1-4 alkylene) NR _a R _b , —NR _a C (═O) R _b , — _{NR a CO 2 R b, -NR} a (C 1~4 _{alkylene) CO 2 R b, = N} -OH, = N-O- alkyl, On reels, cycloalkyl, is selected from the group consisting of heterocyclo, and / heteroaryl, where, R _a, R _b and R _c are is as defined above for substituted alkyl groups, and this compound also optionally Is substituted in the same manner as shown in When the heterocyclo is substituted with a further ring, if the ring by one or two _{(C 1 to 4)} alkyl, _{(C 2 to 4)} alkenyl, halogen, hydroxy, cyano, nitro, _CF 3, O _{(C 1 to 4 alkyl), OCF 3, C (=} O) H, C (= O) (C 1~4 _{alkyl), CO 2 H, CO 2} (C 1~4 alkyl), NHCO ₂ (C _1-4 alkyl), - S _{(C 1-4 alkyl), - NH 2, NH (} C 1~4 alkyl), N _{(C 1-4 alkyl)} 2, N _{(C 1-4 alkyl)} ³ +, SO _{2 (C 1 to 4 alkyl), C (= O) (} C 1~4 _{alkylene) NH 2, C (= O} ) (C 1~4 alkylene) NH (alkyl), and / or C (= O) Substituted with (C _1-4 alkylene) N (C _1-4 alkyl) ₂ .

  Typical monocyclic groups are azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1- Including dioxothienyl and the like. Exemplary bicyclic heterocyclo groups include quinuclidinyl.

を含み、このものは場合により置換され得る。 Preferred heterocyclo groups in the compounds of formula (I) are

Which can be optionally substituted.

The term “heteroaryl” refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups having at least one heteroatom (O, S or N) in at least one ring, 9 or 10 It means a membered bicyclic group and a 11-14 membered tricyclic group. Each ring of a heteroaryl group containing a heteroatom has 1 or 2 oxygen atoms provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom Alternatively, it may contain sulfur atoms and / or 1 to 4 nitrogen atoms. The fused rings completing the bicyclic and tricyclic groups can contain only carbon atoms and can be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms can optionally be oxygenated and the nitrogen atoms can optionally be quaternized. A heteroaryl group that is bicyclic or tricyclic contains at least one fully aromatic ring, while other fused rings can be aromatic or non-aromatic. The heteroaryl group may be attached on any available nitrogen atom or carbon of any ring. The heteroaryl ring system may contain 0, 1, 2, or 3 substituents, which are halogen, trifluoromethyl, trifluoromethoxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, nitro, cyano _{, OR a, SR a, (} = S), - NR a R b, -N ( ^{_{alkyl) 3 +, -NR a SO 2}} , -NR a SO 2 R c, -SO 2 R c, -SO 2 NR _{a R b, -SO 2 NR a} C (= O) R b, SO 3 H, -PO (OH) 2, -C (= O) R a, -CO 2 R a, -C (= O) NR _a R _b , —C (═O) (C _1-4 alkylene) NR _a R _b , —C (═O) NR _a (SO ₂ ) R _b , —CO ₂ (C _1-4 alkylene) NR _a R _{b, -NR a C (= O} ) R b, -NR a CO 2 R b, -NR a (C 1~4 alkylene) _CO 2 R , Aryl, and selected from the group consisting of cycloalkyl, heterocyclo, and / or heteroaryl, wherein the R _a, R _b and R _c be as defined above for substituted alkyl groups, and this compound In some cases, it is substituted in the same manner as shown above. If the heteroaryl is substituted with a further ring, the ring is optionally 1-2 (C _1-4 ) alkyl, (C _2-4 ) alkenyl, halogen, hydroxy, cyano, nitro, CF ₃ , O (C _1-4 alkyl), OCF ₃ , C (═O) H, C (═O) (C _1-4 alkyl), CO ₂ H, CO ₂ (C _1-4 alkyl), NHCO ₂ ( C _1-4 alkyl), —S (C _1-4 alkyl), —NH ₂ , NH (C _1-4 alkyl), N (C _1-4 alkyl) ₂ , N (C _1-4 alkyl) ₃ ⁺ , SO ₂ (C _1-4 alkyl), C (═O) (C _1-4 alkylene) NH ₂ , C (═O) (C _1-4 alkylene) NH (alkyl), and / or C (═O ) (C _1-4 alkylene) N (C _1-4 alkyl) ₂ .

  Typical monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.

  Typical bicyclic heteroaryl groups are indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzoimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl Cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydroisoindolyl, tetrahydroquinolinyl and the like.

  Typical tricyclic heteroaryl groups include carbazolyl, benzoindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

などを含み、これらは場合により、いずれかの利用可能な炭素原子または窒素原子上で置換され得る。 In the compounds of formula (I), preferred heteroaryl groups are

These may optionally be substituted on any available carbon or nitrogen atom.

  Unless specifically stated otherwise, reference to a specifically named aryl (eg, phenyl), cycloalkyl (eg, cyclohexyl), heterocyclo (eg, pyrrolidinyl) or heteroaryl (eg, imidazolyl) is specifically intended. Unless stated otherwise, the reference refers to 0-3, preferably 0-2 substituents (wherein the substituents are as defined above for aryl, cycloalkyl, heterocyclo and / or heteroaryl groups as appropriate). And is selected from the groups shown below.

  The term “heteroatom” includes oxygen, sulfur and nitrogen.

  The term “carbocycle” means a saturated or unsaturated monocyclic or bicyclic ring in which all atoms of all rings are carbon. The term thus includes cycloalkyl and aryl rings. The carbocycle can be substituted, in which case the substituent is selected from the groups indicated above for cycloalkyl and aryl groups.

  When the term “unsaturated” is used in this application to refer to a ring or group, the ring or group may be fully unsaturated or partially unsaturated.

Throughout this application, groups and substituents provide stable molecules and compounds, compounds useful as pharmaceutically acceptable compounds, and / or intermediate compounds useful for preparing pharmaceutically acceptable compounds. As such can be selected by one skilled in the art. For example, in the compound of formula (I) below, the groups: J, M and T are such that two adjacent elements of ring A (defined by J, M and T) are not simultaneously selected from S or O To choose. As a further example, J is defined to be selected from a group containing a heteroalkylene optionally substituted by R ₉ . One skilled in the art can make an appropriate selection for R ₉ as a substituent for the heteroalkylene to provide a stable compound.

［式中、
基：Ａｒ、Ｇ、Ｌ、Ｋ、Ｚ、Ｔ_１、Ｍ_１、Ｔ_２、Ｍ_２、Ｒ_２、Ｒ_４ａおよびＲ_４ｃは、本明細書で定義する通りであって、そしてＪ基は、アルキレン基またはヘテロアルキレン基から選ばれ得る］
を有する化合物を提供し、該化合物は以下の具体的な例を含むが、これらに限定されない。

According to the above definition, the present invention provides compounds of formula (Ia) or (Ib):

[Where:
The groups Ar, G, L, K, Z, T ₁ , M ₁ , T ₂ , M ₂ , R ₂ , R _4a and R _4c are as defined herein, and the J group is May be selected from an alkylene group or a heteroalkylene group]
And the compound includes, but is not limited to, the following specific examples.

  The compounds of formula (I) are capable of forming salts, which are also within the scope of the invention. Unless stated otherwise, it is understood that a reference to a compound of the invention includes a reference to a salt thereof. The term “salt” means acidic and / or basic salts formed with inorganic and / or organic acids or bases. In addition, the term “salt” refers to zwitterionic, for example, when a compound of formula (I) contains both a basic moiety (eg, an amine or pyridine or imidazole ring) and an acidic moiety (eg, a carboxylic acid) It may contain ions (internal ions). Pharmaceutically acceptable (ie, non-toxic and physiologically acceptable) salts, such as acceptable metal and amine salts where the cation does not contribute significantly to the toxicity or biological activity of the salt are preferred. However, other salts may be useful, for example, in isolation or purification steps that can be used during manufacture and are therefore contemplated as being within the scope of the present invention. A salt of a compound of formula (I) can be prepared, for example, by reacting a compound of formula (I) with an amount (eg, an equal amount) of acid or base in a medium in which the salt precipitates or in an aqueous medium, followed by freezing. It can be obtained by drying.

  Typical acid addition salts are acetates (eg, salts formed with acetic acid or trihaloacetic acid (eg, trifluoroacetic acid)), adipates, alginates, ascorbates, aspartates, benzoates , Benzenesulfonate, hydrogen sulfate, boronate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecasulfonate, ethanesulfonate, Fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride (this is formed with hydrochloric acid), hydrobromide (this is Hydrogen bromide together), hydroiodide, 2-hydroxyethane sulfonate, lactate, malate (this forms with malic acid) Methane sulfonate (forms together with methane sulfonic acid), 2-naphthalene sulfonate, nicotinate, nitrate, oxalate, pectate, persulfate, 3-phenylpropionate , Phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (eg, salt formed with sulfuric acid), sulfonate (eg, described herein) Salt), tartrate, thiocyanate, toluenesulfonate (eg, tosylate), undecanoate and the like.

  Typical basic salts are ammonium salts, alkali metal salts (eg, sodium, lithium and potassium salts); alkaline earth metal salts (eg, calcium and magnesium salts); barium, zinc and aluminum salts Organic bases (eg, trialkylamines such as triethylamine, procalin, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephamine, N, N′-dibenzylethylenediamine, dehydroabiethylamine, N-ethylpiperidine, benzyl; Salts with organic amines such as amines, dicyclohexylamine or similar pharmaceutically acceptable amines); and salts with amino acids (eg, arginine, lysine, etc.). Basic nitrogen-containing groups include, for example, lower alkyl halides (eg, methyl, ethyl, propyl and butyl chloride, bromide and iodo), dialkyl sulfates (eg, dimethyl, diethyl, dibutyl and diamyl sulfate), long chains Can be quaternized with aldehydes (eg, decyl, lauryl, myristyl and stearyl chloride, bromide and iodo), aralkyl halides (eg, benzyl and phenethyl bromide) and other reagents. Preferred salts include monohydrochloride, hydrogen sulfide, methanesulfonate, phosphate or nitrate.

Prodrugs and solvates of the compounds of the invention are also contemplated. The term “prodrug” means a compound that upon administration to a subject undergoes a chemical transformation by metabolic or chemical processes to give a compound of formula (I), and / or a salt and / or solvate thereof. . For example, a compound containing a carboxy group forms a physiologically hydrolysable ester, which is hydrolyzed in the body to function as a prodrug to give the compound of formula (I) itself. be able to. Since the hydrolysis reaction often occurs under the influence of digestive enzymes in many cases, it is preferable to administer these prodrugs orally. Parenteral administration can be used when the ester itself is active or when a hydrolysis reaction occurs in the blood. Examples of physiologically hydrolysable esters of compounds of formula (I) include C _1-6 alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C _1-6 alkanoyloxy-C _1-6. Alkyl (eg, acetoxymethyl, pivaloyloxymethyl, or propionyloxymethyl), C _1-6 alkoxycarbonyloxy-C _1-6 alkyl (eg, methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl) , Phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl) -methyl), and other well known physiologically hydrolysable esters (eg, penicillin and cephalo Including those used in the field of sporins) The ester can be produced by a conventional method known in the art.

  The compounds of formula (I) and their salts are in their tautomeric form (in this case the hydrogen atom is transferred to other parts of the molecule and the chemical bonds between the atoms of the molecule are rearranged as a result. ) Can exist. It is to be understood that all tautomeric forms are included within the present invention so long as they can exist. In addition, the compounds of the present invention have trans and cis isomers and may contain one or more chiral centers and therefore exist in enantiomeric and diastereomeric forms. The present invention includes all isomers, as well as mixtures of cis and trans isomers, diastereomeric mixtures, and racemic mixtures of enantiomers (optical isomers). Where no specific description is given of the configuration (cis or trans, or R or S) of the compound (or asymmetric carbon), any one or a mixture of one or more of the isomers Intended. The manufacturing process can use racemates, enantiomers or diastereomers as starting materials. When preparing enantiomeric or diastereomeric products, they can be separated by conventional methods (eg chromatographic methods or fractional crystallization methods). The compounds of the invention can be in free or hydrate form.

  Compounds of formula (I) may also have prodrug forms. Any compound that will be converted in vivo to give the bioactive drug (ie, the compound of formula (I)) is a prodrug within the scope and spirit of the invention.

Various forms of prodrugs are well known in the art. For examples of these prodrug derivatives see:
a) Design of Prodrugs , H. Bundgaard (Elsevier, 1985), and Methods in Enzymology , 42, 309-396, K. Widder et al. (Acamedic Press, 1985);
b) A Textbook of Drug Design and Development , edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5, “Design and Application of Prodrugs”, by H. Bundgaard, pp. 113-191 (1991);
c) H. Bundgaard, Advanced Drug Delivery Reviews , 8, 1-38 (1992).
Each of these forms part of the present specification.

  It should further be understood that solvates (eg hydrates) of the compounds of formula (I) are also within the scope of the invention. Solvation methods are commonly known in the art.

を有する化合物（これは、そのエナンチオマー、ジアステレオマー、医薬的に許容し得る塩、水和物、溶媒和物、およびプロドラッグを含む）である。上記式中、
ＬおよびＫは独立して、ＯまたはＳであり；
Ｚは、ＮまたはＣＲ_４ｂであり；
Ｇは、結合であり；
Ａｒは、ＴまたはＭと直結し、式：

であり；
Ｊは、−Ｏ−、−Ｓ−、−ＮＨ−、−Ｓ(＝Ｏ)−、−ＳＯ_２−、−ＮＨＳＯ_２−、場合により１〜２個のＲ_９で置換されたＣ_１〜３アルキレン、場合により１〜２個のＲ_９で置換されたＣ_２〜３アルケニレンもしくはＣ_１〜２ヘテロアルキレンであり；
Ｔは、ＡｒがＴと結合する場合にはＴ_１であり；そして、ＡｒがＭと結合する場合にはＴ_２であり；
Ｍは、ＡｒがＭと結合する場合にはＭ_１であり；そして、ＡｒがＴと結合する場合にはＭ_２であり；
Ｔ_１およびＭ_１は、−Ｎ−または−ＣＨ−から選ばれ、そしてＴ_２およびＭ_２は、−Ｏ−、−Ｓ−、−ＮＨ−、−Ｓ(＝Ｏ)−、−ＳＯ_２−、−ＮＨＳＯ_２−、−Ｃ(＝Ｏ)−、または−ＣＨ_２−から選ばれ；
但し、Ｊ、ＭおよびＴは、４〜６員の飽和もしくは部分的に不飽和のシクロアルキル、または１〜２個のヘテロ原子を有するヘテロ環を定義するように選択し、ここで、該ヘテロ環の２個の隣接するヘテロ原子は同時に−Ｏ−または−Ｓ−から選ばれることはなく；
Ｒ_１ａおよびＲ_１ｂは独立して、ハロゲン、Ｃ_１〜４アルキル、ヒドロキシ、アルコキシ、ハロアルキル、ハロアルコキシ、シアノ、ニトロ、−ＣＯ_２Ｈ、−Ｃ(＝Ｏ)Ｈ、−ＣＯ_２アルキル、−Ｃ(＝Ｏ)アルキル、−Ｃ(＝Ｏ)ＮＨ(ＣＨ_２)_ｒＣＯ_２Ｈ、−Ｃ(＝Ｏ)ＮＨ(ＣＨ_２)_ｒＣＯ_２(アルキル)、またはＳ(Ｏ)_２アルキルから選ばれるか、あるいは、
フェニル、ベンジル、フェニルオキシ、ベンジルオキシおよびヘテロアリールから選ばれ（ここで、各々のＲ_１ａおよびＲ_１ｂ基は、場合によりいずれかの利用可能な炭素原子または窒素原子上で１〜２個のＣ_１〜４アルキル、ハロゲン、ヒドロキシ、アルコキシ、ハロアルキル、ハロアルコキシ、シアノ、ニトロ、−ＣＯ_２Ｈ、−Ｃ(＝Ｏ)Ｈ、−ＣＯ_２アルキルおよび／または−Ｃ(＝Ｏ)アルキルで置換されるか、あるいは２個のＲ_１ｂ基が互いに一緒になってまたは１個のＲ_１ｂがＲ_１ａと一緒になって縮合ベンゾ環を形成する）；
Ｒ_２は、水素、アルキル、置換アルキル、ＯＲ_１２、ＮＲ_１２Ｒ_１３、Ｃ(＝Ｏ)Ｒ_１２、ＣＯ_２Ｒ_１２、Ｃ(＝Ｏ)ＮＲ_１２Ｒ_１３、ＮＲ_１２Ｃ(＝Ｏ)Ｒ_１３、ＮＲ_１２Ｃ(＝Ｏ)ＯＲ_１３、ＳＲ_１２、Ｓ(Ｏ)_ｐＲ_１３ａ、ＮＲ_１２ＳＯ_２Ｒ_１３ａ、ＳＯ_２ＮＲ_１２Ｒ_１３、シクロアルキル、ヘテロ環、アリールまたはヘテロアリールから選ばれ；
Ｒ_４ａおよびＲ_４ｃは、ハロゲン、アルキル、シアノ、ハロアルキル、ハロアルコキシ、またはニトロであり；
Ｒ_４ｂは、水素、ハロゲン、アルキル、置換アルキル、ニトロ、シアノ、ヒドロキシ、アルコキシ、ハロアルコキシ、フェニルオキシ、−ＣＯ_２Ｈ、−Ｃ(＝Ｏ)Ｈ、ＮＨ(アルキル)、Ｎ(アルキル)_２、ＣＯ_２アルキル、Ｃ(＝Ｏ)アルキル、アルキルチオ、−Ｃ(＝Ｏ)ＮＨ(ＣＨ_２)_ｒＣＯ_２Ｈ、−Ｃ(＝Ｏ)ＮＨ(ＣＨ_２)_ｒＣＯ_２(アルキル)、アリール、ヘテロアリール、またはヘテロ環であり、ここで、該アリール、ヘテロアリールまたはヘテロ環基の各々は場合により、１〜２個のハロゲン、Ｃ_１〜４アルキル、ＯＭｅ、ＣＦ_３、ＣＮ、ＯＣＦ_３、ＣＯ_２Ｈ、−Ｃ(＝Ｏ)Ｈ、ＣＯ_２アルキル、および／またはＣ(＝Ｏ)アルキルで置換され；
Ｒ_９は、−Ａ_１−Ｑ−Ａ_２−Ｒ_１６であり；
Ａ_１は、結合、Ｃ_１〜２アルキレン、またはＣ_２〜３アルケニレンであり；
Ｑは、結合、−Ｃ(＝Ｏ)−、−Ｃ(＝Ｏ)ＮＲ_１７−、−Ｃ(＝Ｓ)ＮＲ_１７−、−ＳＯ_２−、−ＳＯ_２ＮＲ_１７−、−ＣＯ_２−、または−ＮＲ_１７ＣＯ_２−であり；
Ａ_２は、結合、Ｃ_１〜３アルキレン、Ｃ_２〜３アルケニレン、−Ｃ_１〜４アルキレン−ＮＲ_１７−、−Ｃ_１〜４アルキレン−ＮＲ_１７Ｃ(＝Ｏ)−、−Ｃ_１〜４アルキレン−Ｓ−、−Ｃ_１〜４アルキレン−ＳＯ_２−、または−Ｃ_１〜４アルキレン−Ｏ−から選ばれ、ここで、該Ａ_２アルキレン基は分枝または直鎖であり、そして場合により置換基（該置換基は、−ＣＯ_２Ｈ、−ＣＯ_２(Ｃ_１〜４アルキル)、−Ｓ(Ｃ_１〜４アルキル)、ＮＨ_２、−ＮＨ(Ｃ_１〜４アルキル)、または−Ｎ(Ｃ_１〜４アルキル)_２から選ばれる）で置換され；
Ｒ_１２およびＲ_１３は、（ｉ）各々独立して、水素、アルキル、置換アルキル、シクロアルキル、アリール、ヘテロアリール、またはヘテロシクロから選ばれるか；あるいは、（ｉｉ）一緒になってヘテロアリール、またはヘテロシクロを形成し；
Ｒ_１３ａは、アルキル、置換アルキル、シクロアルキル、アリール、ヘテロアリール、またはヘテロシクロであり；
Ｒ_１６は、（ｉ）水素、または場合により１〜３個の置換基（該置換基は、ＯＲ_２３、ＳＲ_２３、−ＣＯ_２Ｒ_２３、−ＳＯ_２(アルキル)、および／またはＮＲ_２３ａＲ_２３ｂである）で置換されたＣ_１〜８アルキルもしくはＣ_２〜８アルケニルから選ばれるか、あるいは、
（ｉｉ）フェニル、ナフチル、５〜１０員の単環もしくは二環のヘテロアリール、４〜１１員の単環もしくは二環のヘテロシクロ、３〜９員の単環もしくは二環のシクロアルキルから選ばれ、ここで各該Ｒ_１６環状基は場合により３個までのＲ_１８で置換され；
Ｒ_１７は、水素、低級アルキル、または置換低級アルキルから選ばれ；
Ｒ_１８は、−(ＣＨ_２)_ｑハロゲン、−(ＣＨ_２)_ｑニトロ、−(ＣＨ_２)_ｑシアノ、−(ＣＨ_２)_ｑハロアルキル、−(ＣＨ_２)_ｑハロアルコキシ、−(ＣＨ_２)_ｑＳＲ_２４、Ｃ_３〜７シクロアルキル、−ＳＯ_２Ｒ_２４、−ＯＲ_２４、−(ＣＨ_２)_ｑＣＯ_２Ｒ_２４、−(ＣＨ_２)_ｑＮＲ_２４Ｒ_２５ 、−(ＣＨ_２)_ｑＮＨＣＯ_２Ｒ_２４、−Ｃ(＝Ｏ)ＮＨ−ＳＯ_２Ｒ_２４、−Ｃ(＝Ｏ)(ＣＨ_２)_ｑＮＲ_２４Ｒ_２５、−Ｏ(ＣＨ_２)_ｒＮＲ_２４Ｒ_２５、−Ｃ(＝Ｏ)Ｒ_２４、−(ＣＨ_２)_ｑＲ_２４、または場合によりＣＯ_２Ｒ_２４で置換された−Ｃ_１〜４アルキルもしくは−Ｃ_２〜４アルケニルから選ばれ；
Ｒ_２３、Ｒ_２３ａおよびＲ_２３ｂは独立して、水素またはアルキルから選ばれ；
Ｒ_２４が−ＳＯ_２Ｒ_２４におけるスルホニル基と結合する場合には、Ｒ_２４は水素でないとう条件で、Ｒ_２４は水素、アルキル、フェニル、ベンジル、Ｃ_３〜７シクロアルキル、５もしくは６員のヘテロアリール、または４〜７員のヘテロシクロから選ばれ、これらは場合により１〜２個の置換基（該置換基は、Ｃ_１〜４アルキル、ハロゲン、ヒドロキシ、トリフルオロメチル、トリフルオロメトキシ、−ＣＯ_２Ｈ、ＣＯ_２Ｃ_１〜４アルキル、Ｃ_１〜４アルコキシ、−Ｓ(Ｃ_１〜４アルキル)、アミノおよび／またはアミノＣ_１〜４アルキルである）で置換され；
Ｒ_２５は、水素またはアルキルから選ばれ；
ｎは、０、１または２であり；
ｐは、１または２であり；
ｑは、０、１、２、３または４であり；そして、
ｒは、１、２、３または４である。 Preferred compounds Preferred compounds are of formula (I):

(Including its enantiomers, diastereomers, pharmaceutically acceptable salts, hydrates, solvates, and prodrugs). In the above formula,
L and K are independently O or S;
Z is N or CR _4b ;
G is a bond;
Ar is directly connected to T or M and has the formula:

Is;
J represents —O—, —S—, —NH—, —S (═O) —, —SO ₂ —, —NHSO ₂ —, optionally substituted with 1 to 2 R ₉ C _1-3. Alkylene, C _2-3 alkenylene or C _1-2 heteroalkylene optionally substituted with 1-2 R ₉ ;
T is T ₁ when Ar binds to T; and T ₂ when Ar binds to M;
M is M ₁ when Ar binds to M; and M ₂ when Ar binds to T;
T ₁ and M ₁ are selected from —N— or —CH—, and T ₂ and M ₂ are —O—, —S—, —NH—, —S (═O) —, —SO ₂ —. , —NHSO ₂ —, —C (═O) —, or —CH ₂ —;
Provided that J, M and T are selected to define a 4-6 membered saturated or partially unsaturated cycloalkyl, or a heterocycle having 1-2 heteroatoms, wherein Two adjacent heteroatoms of the ring are not simultaneously selected from —O— or —S—;
R _1a and R _1b are independently halogen, C _1-4 alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, —CO ₂ H, —C (═O) H, —CO ₂ alkyl, — Selected from C (═O) alkyl, —C (═O) NH (CH ₂ ) _r CO ₂ H, —C (═O) NH (CH ₂ ) _r CO ₂ (alkyl), or S (O) ₂ alkyl Or
Selected from phenyl, benzyl, phenyloxy, benzyloxy and heteroaryl, wherein each R _1a and R _1b group is optionally substituted with 1-2 C on any available carbon or nitrogen atom. _1-4 alkyl, halogen, hydroxy, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, _-CO 2 H, substituted by -C (= O) H, -CO 2 alkyl, and / or -C (= O) alkyl Or two R _1b groups together with each other or one R _1b together with R _1a to form a fused benzo ring);
R ₂ is hydrogen, alkyl, substituted alkyl, OR ₁₂ , NR ₁₂ R ₁₃ , C (═O) R ₁₂ , CO ₂ R ₁₂ , C (═O) NR ₁₂ R ₁₃ , NR ₁₂ C (═O) R ₁₃ , NR ₁₂ C (═O) OR ₁₃ , SR ₁₂ , S (O) _p R _13a , NR ₁₂ SO ₂ R _13a , SO ₂ NR ₁₂ R ₁₃ , cycloalkyl, heterocycle, aryl or heteroaryl ;
R _4a and R _4c are halogen, alkyl, cyano, haloalkyl, haloalkoxy, or nitro;
R _4b is hydrogen, halogen, alkyl, substituted alkyl, nitro, cyano, hydroxy, alkoxy, haloalkoxy, phenyloxy, —CO ₂ H, —C (═O) H, NH (alkyl), N (alkyl) ₂ , CO ₂ alkyl, C (═O) alkyl, alkylthio, —C (═O) NH (CH ₂ ) _r CO ₂ H, —C (═O) NH (CH ₂ ) _r CO ₂ (alkyl), aryl, A heteroaryl, or heterocycle, wherein each of the aryl, heteroaryl or heterocyclic groups is optionally 1-2 halogen, C _1-4 alkyl, OMe, CF ₃ , CN, OCF ₃ , Substituted with CO ₂ H, —C (═O) H, CO ₂ alkyl, and / or C (═O) alkyl;
R ₉ is -A ₁ -QA ₂ -R ₁₆ ;
A ₁ is a bond, C _1-2 alkylene, or C _2-3 alkenylene;
Q is a bond, —C (═O) —, —C (═O) NR ₁₇ —, —C (═S) NR ₁₇ —, —SO ₂ —, —SO ₂ NR ₁₇ —, —CO ₂ —, Or —NR ₁₇ CO ₂ —;
A ₂ is a _{bond, C 1 to 3 alkylene, C 2 to 3 alkenylene, -C 1 to 4} alkylene _-NR 17 _-, - _C 1~4 alkylene _{-NR 17 C (= O) -} , - C 1~4 Selected from alkylene-S—, —C _1-4 alkylene-SO ₂ —, or —C _1-4 alkylene-O—, wherein the A ₂ alkylene group is branched or straight chain, and optionally A substituent (the substituent is —CO ₂ H, —CO ₂ (C _1-4 alkyl), —S (C _1-4 alkyl), NH ₂ , —NH (C _1-4 alkyl), or —N; (C _1-4 alkyl) selected from ₂ );
R ₁₂ and R ₁₃ are each (i) independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo; or (ii) taken together as heteroaryl, or Forming a heterocyclo;
R _13a is alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo;
R ₁₆ is (i) hydrogen, or optionally 1 to 3 substituents (the substituents being OR ₂₃ , SR ₂₃ , —CO ₂ R ₂₃ , —SO ₂ (alkyl), and / or NR _23a R _23b is a) in or selected from _{C 1 to 8} alkyl or _{C 2 to 8} alkenyl substituted, or
(Ii) selected from phenyl, naphthyl, 5-10 membered monocyclic or bicyclic heteroaryl, 4-11 membered monocyclic or bicyclic heterocyclo, 3-9 membered monocyclic or bicyclic cycloalkyl Wherein each said R ₁₆ cyclic group is optionally substituted with up to 3 R ₁₈ ;
R ₁₇ is selected from hydrogen, lower alkyl, or substituted lower alkyl;
R ₁₈ is — (CH ₂ ) _q halogen, — (CH ₂ ) _q nitro, — (CH ₂ ) _q cyano, — (CH ₂ ) _q haloalkyl, — (CH ₂ ) _q haloalkoxy, — (CH ₂ ) _q SR _{24, C 3~7 cycloalkyl, -SO 2 R 24, -OR 24} , - (CH 2) q CO 2 R 24, - (CH 2) q NR 24 R 25, - (CH 2) q NHCO _{2 R 24, -C (= O} ) NH-SO 2 R 24, -C (= O) (CH 2) q NR 24 R 25, -O (CH 2) r NR 24 R 25, -C (= O ) R ₂₄ , — (CH ₂ ) _q R ₂₄ , or —C _1-4 alkyl or —C _2-4 alkenyl optionally substituted with CO ₂ R ₂₄ ;
R ₂₃ , R _23a and R _23b are independently selected from hydrogen or alkyl;
When the R ₂₄ is bonded to the sulfonyl group in _-SO 2 _{R 24 is, R 24} is Naito conditions with _{hydrogen, R 24} is hydrogen, alkyl, phenyl, _{benzyl, C 3 to 7} cycloalkyl, a 5 or 6-membered selected from heterocyclo heteroaryl or 4-7 membered, these are optionally one to two substituents (the substituents, C _{1 to 4} alkyl, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, - Substituted with CO ₂ H, CO ₂ C _1-4 alkyl, C _1-4 alkoxy, —S (C _1-4 alkyl), amino and / or amino C _1-4 alkyl);
R ₂₅ is selected from hydrogen or alkyl;
n is 0, 1 or 2;
p is 1 or 2;
q is 0, 1, 2, 3 or 4; and
r is 1, 2, 3 or 4.

が好ましい。上記式中、Ｒ_１ａは、ハロゲン、シアノ、ハロアルキル、ハロアルコキシ、または場合により置換されたフェニルもしくはヘテロアリールであることが好ましく、そしてＲ_１ｂは存在しないか、またはハロゲン、Ｃ_１〜４アルキル、ヒドロキシ、アルコキシ、ハロアルキル、ハロアルコキシ、シアノ、ニトロ、−ＣＯ_２Ｈ、−Ｃ(＝Ｏ)Ｈ、−ＣＯ_２アルキル、−Ｃ(＝Ｏ)アルキル、−Ｃ(＝Ｏ)ＮＨ(ＣＨ_２)_１〜４ＣＯ_２Ｈ、または−Ｃ(＝Ｏ)ＮＨ(ＣＨ_２)_１〜４ＣＯ_２(アルキル)からなる群から選ばれる。あるいは、２個のＲ_１ｂ基は互いに一緒になってまたは１個のＲ_１ｂはＲ_１ａと一緒になり得て、縮合ベンゾ環を形成する。 In the compound of formula (I), the group Ar is

Is preferred. Wherein R _1a is preferably halogen, cyano, haloalkyl, haloalkoxy, or optionally substituted phenyl or heteroaryl, and R _1b is absent or is halogen, C _1-4 alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cyano, _{nitro, -CO 2 H, -C (=} O) H, -CO 2 alkyl, -C (= O) alkyl, -C (= O) NH (CH _{2) It} is selected from the group consisting of _1-4 CO ₂ H, or —C (═O) NH (CH ₂ ) _1-4 CO ₂ (alkyl). Alternatively, two R _1b groups can be taken together or one R _1b can be taken together with R _1a to form a fused benzo ring.

In the compounds of formula (I), the R _4a and R _4c groups are preferably selected from halogen, alkyl, cyano, nitro, haloalkyl, haloalkyl, aryloxy, or arylthio, and both R _4a and R _4c are chlorine It is more preferable.

  In the compounds of formula (I), the G group is preferably a bond; the L and K groups are preferably oxygen; and the Z group is preferably CH.

In the compound of formula (I), the T group is preferably T ₁ and is CH, the M group is preferably M ₂ and is CH ₂ and the J group is optionally substituted. C ₁ heteroalkylene is preferred, so that A is a 5-membered ring and the J group is more preferably a —CH ₂ —NR ₉ — group.

In the compounds of formula (I), the R ₂ group is preferably C (═O) lower alkyl, or C _1-6 alkyl optionally substituted with CO ₂ H or CO ₂ (alkyl), and R ₂ More preferably, the group is methyl.

に記載の化合物、並びにそれらの医薬的に許容し得る塩、水和物およびプロドラッグもまた好ましい。上記式中、
ＬおよびＫは独立して、ＯまたはＳであり；
Ｊは、−Ｏ−、−Ｓ−、−ＮＨ−、−Ｓ(＝Ｏ)−、−ＳＯ_２−、−ＮＨＳＯ_２−、場合により置換されたＣ_１〜３アルキレン、場合により置換されたＣ_２〜３アルケニレン、または場合により置換されたＣ_１〜２ヘテロアルキレンであり；
Ｔは、−Ｎ−または−ＣＨ−であり；
Ｒ_１ａは、ハロゲン、シアノ、または場合により置換されたフェニルもしくはヘテロアリールであり；
Ｒ_１ｂは、ハロゲン、Ｃ_１〜４アルキル、ヒドロキシ、アルコキシ、ハロアルキル、ハロアルコキシ、シアノ、ニトロ、−ＣＯ_２Ｈ、−Ｃ(＝Ｏ)Ｈ、−ＣＯ_２アルキル、−Ｃ(＝Ｏ)アルキル、−Ｃ(＝Ｏ)ＮＨ(ＣＨ_２)_１〜４ＣＯ_２Ｈ、もしくは−Ｃ(＝Ｏ)ＮＨ(ＣＨ_２)_１〜４ＣＯ_２(アルキル)；または、場合により１〜２個の置換基（該置換基は、Ｃ_１〜４アルキル、ハロゲン、ヒドロキシ、アルコキシ、ハロアルキル、ハロアルコキシ、シアノ、ニトロ、−ＣＯ_２Ｈ、−Ｃ(＝Ｏ)Ｈ、−ＣＯ_２アルキル、および／または−Ｃ(＝Ｏ)アルキルである）で置換されたフェニル、ベンジル、フェニルオキシ、ベンジルオキシもしくはヘテロアリールから選ばれ；
Ｒ_２は、水素、アルキル、置換アルキル、Ｏ(Ｃ_１〜４アルキル)、アミノ、ＮＨ(Ｃ_１〜４アルキル)、Ｎ(アルキル)_２、Ｃ(＝Ｏ)Ｈ、Ｃ(＝Ｏ)アルキル、ＣＯ_２(アルキル)、ＳＯ_２アルキル、Ｃ_３〜６シクロアルキル、ヘテロ環、アリール、またはヘテロアリールから選ばれ；
Ｒ_４ａおよびＲ_４ｃは、ハロゲン、アルキル、シアノ、トリフルオロメチル、またはニトロであり；そして、
ｎは、０、１または２である。 Formula (Ic)

Also preferred are the compounds described in 1) and their pharmaceutically acceptable salts, hydrates and prodrugs. In the above formula,
L and K are independently O or S;
J is —O—, —S—, —NH—, —S (═O) —, —SO ₂ —, —NHSO ₂ —, optionally substituted C _1-3 alkylene, optionally substituted C _2-3 alkenylene, or optionally substituted C _1-2 heteroalkylene;
T is -N- or -CH-;
R _1a is halogen, cyano, or optionally substituted phenyl or heteroaryl;
R _1b is halogen, C _1-4 alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, —CO ₂ H, —C (═O) H, —CO ₂ alkyl, —C (═O) alkyl. , -C (= O) NH ( CH 2) 1~4 CO 2 H or -C, (= O) NH ( CH 2) 1~4 CO 2 ( alkyl); or, optionally one to two substituents Groups (the substituents are C _1-4 alkyl, halogen, hydroxy, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, —CO ₂ H, —C (═O) H, —CO ₂ alkyl, and / or — Selected from phenyl, benzyl, phenyloxy, benzyloxy or heteroaryl substituted with C (═O) alkyl);
R ₂ is hydrogen, alkyl, substituted alkyl, O (C _1-4 alkyl), amino, NH (C _1-4 alkyl), N (alkyl) ₂ , C (═O) H, C (═O) alkyl , CO ₂ (alkyl), SO ₂ alkyl, C _3-6 cycloalkyl, heterocycle, aryl, or heteroaryl;
R _4a and R _4c are halogen, alkyl, cyano, trifluoromethyl, or nitro; and
n is 0, 1 or 2.

In a compound of formula (Ic) as defined immediately above,
J _{is, -CH 2 -, - CH 2} -CH (R 9) -, or _-CH 2 -N _{(R 9)} -, more preferably, wherein,
R ₉ is -A ₁ -QA ₂ -R ₁₆ ;
A ₁ is a bond, C _1-2 alkylene, or C _2-3 alkylene;
Q is a bond, —C (═O) —, —C (═O) NR ₁₇ —, —SO ₂ —, —CO ₂ —, or —NR ₁₇ CO ₂ —;
A ₂ is a _{bond, C 1 to 2 alkylene, C 2 to 3 alkenylene, -C 1 to 4} alkylene _-NR 17 _-, - _C 1~4 an alkylene _{-NR 17 C (= O) -} , - C 1~4 Alkylene-S—, —C _1-4 alkylene-SO ₂ —, or —C _1-4 alkylene-O—, wherein the A ₂ alkylene group is branched or straight chain, and optionally —CO Selected from ₂ H, —CO ₂ (C _1-4 alkyl), —S (C _1-4 alkyl), NH ₂ , —NH (C _1-4 alkyl), or —N (C _1-4 alkyl) ₂ Substituted with
R ₁₆ is
(A) hydrogen or optionally one to two substituents, (the substituents, OH, _{O (C 1 to 4 alkyl), - CO 2 H, -CO} 2 (C 1~4 alkyl), NH ₂ , -NH _{(C 1 to 4} alkyl), and / or N _{(C 1 to 4 alkyl) 2} is) _{C 1 to 6} alkyl or _{C 2 to 6} alkenyl substituted with or,
(B) furanyl, indolyl, carbazolyl, pyrazolyl, pyrrolyl, thienyl, pyridyl, pyrimidinyl, benzofuranyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, phenyl, piperidyl, pyrrolidinyl, pyridazinyl, C _3-7 cycloalkyl, piperazinyl, thiazolyl, morpholinyl, 1,2,5,6-tetrahydropyridyl, quinoxalinyl, benzothiazolyl, benzotriazolyl, benzodioxanyl, benzooxadiazolyl, thienopyrazolyl, tetrahydroquinolinyl, or quinolinyl (where each said cyclic R ₁₆ group Optionally substituted with up to 3 R ₁₈ )
Chosen from;
R ₁₇ is selected from hydrogen, lower alkyl, or substituted lower alkyl;
R ₁₈ is —C _1-4 alkyl, —S (C _1-4 alkyl), C _3-7 cycloalkyl, —SO ₂ (C _1-4 alkyl), —O (C _1-4 alkyl), — SO ₂ -phenyl, halogen, hydroxy, nitro, cyano, — (CH ₂ ) _q CO ₂ H, — (CH ₂ ) _q CO ₂ C _1-4 alkyl, — (CH ₂ ) _q NH ₂ , —O (CH _{2) q CO 2 H, -CH} = CH-CO 2 H, -CH = CH-CO 2 ( _{alkyl), - (CH 2) q} NH ( _{alkyl), - (CH 2) q} NHCO 2 alkyl, - ( C═O) NH—SO ₂ alkyl, — (CH ₂ ) _q NH (benzyl), — (CH ₂ ) _q N (alkyl) ₂ , —O (CH ₂ ) _r N (alkyl) ₂ , —O benzyl, _{-C (= O) (CH 2} ) q NH 2, -C (= O) (CH 2) q NH ( alkyl), - C (= O) (CH 2) q N ( alkyl _{Le) 2, -O (CH 2)} r NH 2, -O (CH 2) r NH ( _{alkyl), - O (CH 2)} r N ( _alkyl) 2, -C (= _O) pyridyl, - (CH _{2) q} phenyl, - (CH _{2) q} pyridyl, - (CH _{2) q} triazolyl, - (CH _{2) q} tetrazolyl, - (CH _{2) q} imidazolyl, - (CH _{2) q} pyrazolyl, - (CH _{2) q} thiamorpholinyl, — (CH ₂ ) _q morpholinyl, — (CH ₂ ) _q thienyl, — (CH ₂ ) _q pyrazinyl, wherein each R ₁₈ alkyl group or cyclic group is optionally 1 to 2 substituents (the substituents are C _1-4 alkyl, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, —CO ₂ H, CO ₂ C _1-4 alkyl, C _1-4 alkoxy, — S _{(C 1 to 4} alkyl), amino, and / or Substituted with an amino _{C 1 to 4} alkyl):
q is 0, 1, 2, 3 or 4; and
r is 1, 2, 3 or 4.

R ₉ is —C _1-4 alkylene-R ₁₆ , —C (═O) R ₁₆ , or —C (═O) C _1-4 alkylene-R ₁₆ , more preferably —CH ₂ R _16. Further preferred are compounds as defined immediately above, wherein R ₁₆ is as defined immediately above, more preferably thienyl, phenyl or pyridyl optionally substituted with 1-2 R ₁₈ .

に記載する化合物、並びにその医薬的に許容し得る塩、水和物およびプロドラッグもまた好ましい。上記式中、
Ｊは、−(ＣＲ_９ａＲ_９ｂ)_ｘ−または−(ＣＲ_９ａＲ_９ｂ)_ｙ−ＮＲ_９ｃ−(ＣＲ_９ａＲ_９ｂ)_ｚ−（式中、ｙおよびｚは合わせて２を越えないという条件で、ｘは１、２または３であり、ｙは０、１または２であり、そしてｚは０、１または２である）であり；
Ｔ_１は、−Ｎ−または−ＣＨ−であり；
Ｒ_１ａは、水素、シアノ、ニトロ、トリフルオロメチル、ＯＣＦ_３、ヘテロシクロまたはヘテロアリールであり；
Ｒ_１ｂは、水素、ハロゲン、Ｃ_１〜４アルキル、シアノ、ニトロ、−ＣＯ_２Ｈ、−Ｃ(＝Ｏ)Ｈ、−ＣＯ_２アルキル、または−Ｃ(＝Ｏ)アルキルであり；
Ｒ_２は、水素、Ｃ_１〜４アルキル、アミノ、ＮＨ(Ｃ_１〜４アルキル)、Ｎ(アルキル)_２、Ｃ(＝Ｏ)Ｈ、Ｃ(＝Ｏ)Ｃ_１〜４アルキル、ＣＯ_２(Ｃ_１〜４アルキル)、ＳＯ_２Ｃ_１〜４アルキル_、Ｃ_３〜６シクロアルキル、ヘテロ環、アリール、ヘテロアリール、または１〜３個の置換基（該置換基は、アミノ、ＮＨ(Ｃ_１〜４アルキル)、Ｎ(アルキル)_２、Ｃ(＝Ｏ)Ｈ、Ｃ(＝Ｏ)Ｃ_１〜４アルキル、ＣＯ_２Ｈ、ＣＯ_２(Ｃ_１〜４アルキル)、ＳＯ_２Ｃ_１〜４アルキル、ＳＯ_３Ｈおよび／またはＰＯ(ＯＨ)_２である）で置換されたＣ_１〜４アルキルから選ばれ；
Ｒ_９ａおよびＲ_９ｂは各々独立して、水素、ハロゲン、Ｃ_１〜４アルキル、置換アルキル、ヒドロキシ、アルコキシ、ハロアルキル、ハロアルコキシ、シアノ、ニトロ、−ＣＯ_２Ｈ、−Ｃ(＝Ｏ)Ｈ、−ＣＯ_２アルキル、−Ｃ(＝Ｏ)アルキル、−Ｃ(＝Ｏ)ＮＨ(ＣＨ_２)_１〜４ＣＯ_２Ｈ、および／または−Ｃ(＝Ｏ)ＮＨ(ＣＨ_２)_１〜４ＣＯ_２(アルキル)から選ばれるか、あるいは、Ｒ_９ａおよびＲ_９ｂは一緒になってケト（＝Ｏ）を形成し；
Ｒ_９ｃは、ハロゲン、Ｃ_１〜４アルキル、置換アルキル、ヒドロキシ、アルコキシ、ハロアルキル、ハロアルコキシ、ＳＯ_２Ｒ_１６、Ｃ(＝Ｏ)Ｒ_１６、ＳＯ_２ＮＲ_１６Ｒ_１７、ＣＯ_２Ｒ_１６、−Ｃ(＝Ｓ)ＮＲ_１６Ｒ_１７、Ｃ(＝Ｏ)Ｃ(＝Ｏ)Ｒ_１６、Ｃ(＝Ｏ)ＮＨ(ＣＨ_２)_１〜４ＣＯ_２Ｈ、−Ｃ(＝Ｏ)ＮＨ(ＣＨ_２)_１〜４ＣＯ_２(アルキル)、フェニル、Ｃ_３〜７シクロアルキル、または５〜６員のヘテロアリールもしくはヘテロシクロから選ばれ；
Ｒ_１６が−ＳＯ_２Ｒ_１６の通りスルホニル基と結合する場合には、Ｒ_１６は水素ではないという条件で、Ｒ_１６およびＲ_１７は、水素、低級アルキル、置換アルキル、フェニル、Ｃ_３〜７シクロアルキル、５〜６員のヘテロアリール、５〜６員のヘテロシクロ、または９から０員のアリールもしくはヘテロアリール（これらは場合により、１〜２個のＣ_１〜４アルキル、ハロゲン、ニトロ、シアノ、アミノ、Ｃ_１〜４アミノアルキル、Ｃ_１〜４チオアルキル、ヒドロキシ、Ｃ_１〜４アルコキシ、−ＣＯ_２Ｈ、−ＣＯ_２(アルキル)、−Ｃ(＝Ｏ)Ｈ、−Ｃ(＝Ｏ)アルキル、−Ｃ(＝Ｏ)(ＣＨ_２)_ｑＮＨ_２、フェニル、Ｃ_３〜７シクロアルキル、５〜６員のヘテロアリール、および／または５〜６員のヘテロシクロで置換される）から選ばれ；そして、
ｑは、０、１または２である。 Formula (Id):

Also preferred are the compounds described in 1) and pharmaceutically acceptable salts, hydrates and prodrugs thereof. In the above formula,
J is — (CR _9a R _9b ) _x — or — (CR _9a R _9b ) _y —NR _9c — (CR _9a R _9b ) _z — (wherein y and z together do not exceed 2) , X is 1, 2 or 3, y is 0, 1 or 2 and z is 0, 1 or 2);
T ₁ is —N— or —CH—;
R _1a is hydrogen, cyano, nitro, trifluoromethyl, OCF ₃ , heterocyclo or heteroaryl;
R _1b is hydrogen, halogen, C _1-4 alkyl, cyano, nitro, —CO ₂ H, —C (═O) H, —CO ₂ alkyl, or —C (═O) alkyl;
R ₂ is hydrogen, C _1-4 alkyl, amino, NH (C _1-4 alkyl), N (alkyl) ₂ , C (═O) H, C (═O) C _1-4 alkyl, CO ₂ ( C _1-4 alkyl), SO ₂ C _1-4 alkyl _, C _3-6 cycloalkyl, heterocycle, aryl, heteroaryl, or 1 to 3 substituents (the substituents are amino, NH (C _{1 to 4} alkyl), N _{(alkyl) 2, C (= O)} H, C (= O) C 1~4 _{alkyl, CO 2 H, CO 2 (} C 1~4 _alkyl), SO _{2 C 1~4} alkyl Selected from C _1-4 alkyl substituted with SO ₃ H and / or PO (OH) ₂ ;
R _9a and R _9b are each independently hydrogen, halogen, C _1-4 alkyl, substituted alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, —CO ₂ H, —C (═O) H, —CO ₂ alkyl, —C (═O) alkyl, —C (═O) NH (CH ₂ ) _1-4 CO ₂ H, and / or —C (═O) NH (CH ₂ ) _1-4 CO _2. Or selected from (alkyl) or R _9a and R _9b together form a keto (═O);
R _9c is halogen, C _1-4 alkyl, substituted alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, SO ₂ R ₁₆ , C (═O) R ₁₆ , SO ₂ NR ₁₆ R ₁₇ , CO ₂ R ₁₆ , − C (═S) NR ₁₆ R ₁₇ , C (═O) C (═O) R ₁₆ , C (═O) NH (CH ₂ ) _1-4 CO ₂ H, —C (═O) NH (CH ₂ ) _1-4 CO ₂ (alkyl), phenyl, C _3-7 cycloalkyl, or 5-6 membered heteroaryl or heterocyclo;
When the R ₁₆ is bonded to as the sulfonyl group _-SO 2 _{R 16 is} with the proviso that _{R 16} is not _{hydrogen, R 16} and _{R 17} is hydrogen, lower alkyl, substituted alkyl, _{phenyl, C 3 to 7} Cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclo, or 9-0 membered aryl or heteroaryl (these are optionally 1-2 C _1-4 alkyl, halogen, nitro, cyano , Amino, C _1-4 aminoalkyl, C _1-4 thioalkyl, hydroxy, C _1-4 alkoxy, —CO ₂ H, —CO ₂ (alkyl), —C (═O) H, —C (═O) alkyl, -C (= O) (CH 2) q NH 2, _{phenyl, C 3 to 7} cycloalkyl, 5-6 membered heteroaryl, and / or 5-6 membered selected from to) substituted heterocyclo Re; and,
q is 0, 1 or 2.

As defined above, in the compound of formula (Id), y is preferably 1 or 2, T ₁ is preferably —CH—, and R ₂ is hydrogen or C _1-4 alkyl. And R _9a and R _9b are preferably hydrogen.

R _9c is -A ₁ -QA ₂ -R ₁₆ and A ₁ , Q, A ₂ and R ₁₆ are as defined above for compounds of formula (Ic) Also preferred are compounds of (Id).

を有する化合物、そのエナンチオマー、ジアステレオマーまたは塩である。上記式中、
Ｒ_１ａは、ハロゲン、シアノ、ニトロ、トリフルオロメチル、ＯＣＦ_３、ヘテロアリールまたはヘテロシクロであり；
Ｒ_１ｂは、水素、ハロゲン、Ｃ_１〜４アルキル、シアノ、ニトロ、−ＣＯ_２Ｈ、−Ｃ(＝Ｏ)Ｈ、−ＣＯ_２アルキル、または−Ｃ(＝Ｏ)アルキルであり；
Ｒ_２は、水素またはＣ_１〜４アルキルであり；
Ｒ_９は、水素、Ｃ_１〜１０アルキル、Ｃ_２〜１０アルケニル、ヒドロキシ、アルコキシ、アルキルチオ、ハロアルキル、ハロアルコキシ、フェニル、Ｃ_３〜６シクロアルキル、フェニル、ピリジル、ピリダジニル、ピリミジニル、−(ＣＨ_２)_ｓフェニル、−(ＣＨ_２)_ｓテトラゾリル、−(ＣＨ_２)_ｓピリジル、−(ＣＨ_２)_ｓチエニル、−(ＣＨ_２)_ｓカルバゾリル、−(ＣＨ_２)_ｓインドリル、−(ＣＨ_２)_ｓフリル、−(ＣＨ_２)_ｓキノリル、−(ＣＨ_２)_ｓＣ_３〜６シクロアルキル、−(ＣＨ_２)_ｓチアゾリル、−(ＣＨ_２)_ｓピロリル、−(ＣＨ_２)_ｓイミダゾリル、−(ＣＨ_２)_ｓイソキサゾリル、−(ＣＨ_２)_ｓベンゾフリル、−(ＣＨ_２)_ｓピラゾリル、−Ｃ(＝Ｏ)Ｈ、−Ｃ(＝Ｏ)(アルキル)、−Ｃ(＝Ｏ)Ｃ_１〜１０アルキル、−Ｃ(＝Ｏ)フェニル、−Ｃ(＝Ｏ)ピペリジル、−Ｃ(＝Ｏ)モルホリニル、−Ｃ(＝Ｏ)Ｃ_３〜６シクロアルキル、−Ｃ(＝Ｏ)ピロリジニル、−Ｃ(＝Ｏ)キノリル、−Ｃ(＝Ｏ)イミダゾリル、−Ｃ(＝Ｏ)ピラゾリル、−Ｃ(＝Ｏ)チアゾリル、−Ｃ(＝Ｏ)キノキサリニル、−Ｃ(＝Ｏ)ピリジル、−Ｃ(＝Ｏ)−１,２,５,６−テトラヒドロピリジル、−Ｃ(＝Ｏ)ベンゾチアゾリル、−Ｃ(＝Ｏ)ベンゾトリアゾリル、−Ｃ(＝Ｏ)ベンゾジオキサニル、−Ｃ(＝Ｏ)ベンゾオキサジアゾリル、−Ｃ(＝Ｏ)１,２,３,４−テトラヒドロキノリル、−Ｃ(＝Ｏ)チエノピラゾリル、−Ｃ(＝Ｏ)(ＣＨ_２)_ｓテトラゾリル、−Ｃ(＝Ｏ)(ＣＨ_２)_ｓピリジル、−Ｃ(＝Ｏ)(ＣＨ_２)_ｓフェニル、−Ｃ(＝Ｏ)(ＣＨ_２)_ｓピロリジニル、−Ｃ(＝Ｏ)(ＣＨ_２)_ｓピペリジル、−Ｃ(＝Ｏ)ＣＨ＝ＣＨ(フェニル)、−Ｃ(＝Ｏ)ＣＨ＝ＣＨ(ピリジル)、−Ｃ(＝Ｏ)ＣＨ_２Ｏ(アルキル)、−Ｃ(＝Ｏ)ＣＨ_２Ｓ(アルキル)、−Ｃ(＝Ｏ)ＣＨ_２Ｓ(ピリジル)、−Ｃ(＝Ｏ)ＣＨ_２ＳＯ_２(アルキル)、−Ｃ(＝Ｏ)ＣＨ_２ＳＯ_２(フェニル)、−Ｃ(＝Ｏ)ＣＨ_２ＮＨ(フェニル)、−Ｃ(＝Ｏ)ＣＨ_２ＮＨ(ベンジル)、−Ｃ(＝Ｏ)ＣＨ_２ＮＨ(チアゾリル)、−Ｃ(＝Ｏ)ＣＨ_２ＮＨＣ(＝Ｏ)ピリジル、−Ｃ(＝Ｏ)ＣＨ_２ＮＨＣ(＝Ｏ)フェニル、−(ＣＨ_２)_ｔＳＯ_２(アルキル)、−(ＣＨ_２)_ｔＳＯ_２(フェニル)、−(ＣＨ_２)_ｔＳＯ_２(チエニル)、−(ＣＨ_２)_ｔＳＯ_２(イミダゾリル)、−(ＣＨ_２)_ｔＳＯ_２(フリル)、−(ＣＨ_２)_ｔＳＯ_２(ピロリル)、ＳＯ_２ＮＨ(フェニル)、−Ｃ(＝Ｓ)ＮＨ_２、−Ｃ(＝Ｓ)ＮＨ(アルキル)、−Ｃ(＝Ｓ)ＮＨ(フェニル)、−(ＣＨ_２)Ｃ(＝Ｏ)ピロリジニル、−(ＣＨ_２)Ｃ(＝Ｏ)ピペリジル、−(ＣＨ_２)Ｃ(＝Ｏ)ピペラジニル、−ＣＯ_２(アルキル)、−ＣＯ_２(フェニル)、−ＣＯ_２(ベンジル)、ＮＨＣＯ_２(アルキル)、−(ＣＨ_２)_ｔＣ(＝Ｏ)ＮＨ(フェニル)、−(ＣＨ_２)_ｔＣ(＝Ｏ)ＮＨ(ピペリジル)、−(ＣＨ_２)_ｔＣ(＝Ｏ)ＮＨ(チエニル)、−(ＣＨ_２)_ｔＣ(＝Ｏ)ＮＨ(チアゾリル)、−(ＣＨ_２)_ｔＣ(＝Ｏ)ＮＨ(Ｃ_５〜６シクロアルキル)、−(ＣＨ_２)_ｔＣ(＝Ｏ)ＮＨ(ベンジル)、−(ＣＨ_２)_ｔＣ(＝Ｏ)ＮＨ(ピロリジニル)、−(ＣＨ_２)_ｔＣ(＝Ｏ)ＮＨ(ピペラジニル)、−(ＣＨ_２)_ｔＣ(＝Ｏ)ＮＨ_２、−(ＣＨ_２)_ｔＣ(＝Ｏ)ＮＨ(アルキル)、−(ＣＨ_２)_ｔＣ(＝Ｏ)Ｎ(アルキル)_２、−(ＣＨ_２)_ｔＣ(＝Ｏ)Ｎ(Ｃ_１〜４アルキル)(フェニル)、−(ＣＨ_２)_ｔＣ(＝Ｏ)Ｎ(Ｃ_１〜４アルキル)(チエニル)、−(ＣＨ_２)_ｔＣ(＝Ｏ)Ｎ(Ｃ_１〜４アルキル)(チアゾリル)、−(ＣＨ_２)_ｔＣ(＝Ｏ)Ｎ(Ｃ_１〜４アルキル)(ベンジル)、または−(ＣＨ_２)_ｔＣ(＝Ｏ)Ｎ(Ｃ_１〜４アルキル)ＣＯ_２(アルキル)から選ばれ、ここで、各Ｒ_９の各々のアルキル基、アルケニル基または環状基は場合により３個までのＲ_１８で置換され；
Ｒ_１８は、−Ｃ_１〜４アルキル、−Ｓ(Ｃ_１〜４アルキル)、Ｃ_３〜７シクロアルキル、−ＳＯ_２(Ｃ_１〜４アルキル)、−Ｏ(Ｃ_１〜４アルキル)、−ＳＯ_２−フェニル、ハロゲン、ヒドロキシ、ニトロ、シアノ、−(ＣＨ_２)_ｑＣＯ_２Ｈ、−(ＣＨ_２)_ｑＣＯ_２Ｃ_１〜４アルキル、−(ＣＨ_２)_ｑＮＨ_２、−Ｏ(ＣＨ_２)_ｑＣＯ_２Ｈ、−ＣＨ＝ＣＨ−ＣＯ_２Ｈ、−ＣＨ＝ＣＨ−ＣＯ_２(アルキル)、−(ＣＨ_２)_ｑＮＨ(アルキル)、−(ＣＨ_２)_ｑＮＨＣＯ_２アルキル、−(Ｃ＝Ｏ)ＮＨ−ＳＯ_２アルキル、−(ＣＨ_２)_ｑＮＨ(ベンジル)、−(ＣＨ_２)_ｑＮ(アルキル)_２、−Ｏ(ＣＨ_２)_ｒＮ(アルキル)_２、−Ｏベンジル、−Ｃ(＝Ｏ)(ＣＨ_２)_ｑＮＨ_２、−Ｃ(＝Ｏ)(ＣＨ_２)_ｑＮＨ(アルキル)、−Ｃ(＝Ｏ)(ＣＨ_２)_ｑＮ(アルキル)_２、−Ｏ(ＣＨ_２)_ｒＮＨ_２、−Ｏ(ＣＨ_２)_ｒＮＨ(アルキル)、−Ｏ(ＣＨ_２)_ｒＮ(アルキル)_２、−Ｃ(＝Ｏ)ピリジル、−(ＣＨ_２)_ｑフェニル、−(ＣＨ_２)_ｑピリジル、−(ＣＨ_２)_ｑトリアゾリル、−(ＣＨ_２)_ｑテトラゾリル、−(ＣＨ_２)_ｑイミダゾリル、−(ＣＨ_２)_ｑピラゾリル、−(ＣＨ_２)_ｑチアモルホリニル、−(ＣＨ_２)_ｑモルホリニル、−(ＣＨ_２)_ｑチエニル、−(ＣＨ_２)_ｑピラジニルから選ばれ、ここで、各Ｒ_１８の各々のアルキル基または環状基は場合により１〜２個のＣ_１〜４アルキル、ハロゲン、ヒドロキシ、トリフルオロメチル、トリフルオロメトキシ、−ＣＯ_２Ｈ、ＣＯ_２Ｃ_１〜４アルキル、Ｃ_１〜４アルコキシ、−Ｓ(Ｃ_１〜４アルキル)、アミノおよび／またはアミノＣ_１〜４アルキルで置換され；
ｎは、０、１または２であり；
ｑは、０、１、２、３または４であり；
ｒは、１、２、３または４であり；
ｓは、１、２、３または４であり；そして、
ｔは、０、１または２である。 In another embodiment of the present invention, preferred compounds are of formula (Ie):

Or an enantiomer, diastereomer or salt thereof. In the above formula,
R _1a is halogen, cyano, nitro, trifluoromethyl, OCF ₃ , heteroaryl or heterocyclo;
R _1b is hydrogen, halogen, C _1-4 alkyl, cyano, nitro, —CO ₂ H, —C (═O) H, —CO ₂ alkyl, or —C (═O) alkyl;
R ₂ is hydrogen or C _1-4 alkyl;
R ₉ is hydrogen, C _1-10 alkyl, C _2-10 alkenyl, hydroxy, alkoxy, alkylthio, haloalkyl, haloalkoxy, phenyl, C _3-6 cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, — (CH ₂ ) _s phenyl, - (CH _{2) s} tetrazolyl, - (CH _{2) s} pyridyl, - (CH _{2) s} thienyl, - (CH _{2) s} carbazolyl, - (CH _{2) s} indolyl, - (CH _{2) s} furyl, - (CH _{2) s} quinolyl, - (CH _{2) s} C _{3 to 6} cycloalkyl, - (CH _{2) s} thiazolyl, - (CH _{2) s} pyrrolyl, - (CH _{2) s} imidazolyl, - (CH _{2) s} isoxazolyl, - (CH _{2) s} benzofuryl, - (CH _{2) s} pyrazolyl, -C (= O) H, -C (= O) ( alkyl), - C (= O) C 1~10 alkyl ,- (= O) phenyl, -C (= O) piperidyl, -C (= O) _morpholinyl, -C (= O) _C 3~6 cycloalkyl, -C (= O) pyrrolidinyl, -C (= O) quinolyl -C (= O) imidazolyl, -C (= O) pyrazolyl, -C (= O) thiazolyl, -C (= O) quinoxalinyl, -C (= O) pyridyl, -C (= O) -1, 2,5,6-tetrahydropyridyl, -C (= O) benzothiazolyl, -C (= O) benzotriazolyl, -C (= O) benzodioxanyl, -C (= O) benzooxadiazolyl, -C (= O) 1,2,3,4- tetrahydroquinolyl, -C (= O) thieno-pyrazolyl, -C (= O) (CH 2) s tetrazolyl, -C (= O) (CH 2) _s pyridyl, -C (= O) (CH 2) s phenyl, -C (= O) (CH 2) s pyrrolidinyl, -C (= O) (CH 2) s piperidyl, -C (= O) CH = CH (Phenyl), - C (= O) CH = CH ( pyridyl), - C (= O) CH 2 O ( alkyl), - C (= O) CH 2 S ( alkyl), - C (= O) CH ₂ S (pyridyl), —C (═O) CH ₂ SO ₂ (alkyl), —C (═O) CH ₂ SO ₂ (phenyl), —C (═O) CH ₂ NH (phenyl), —C ( ═O) CH ₂ NH (benzyl), —C (═O) CH ₂ NH (thiazolyl), —C (═O) CH ₂ NHC (═O) pyridyl, —C (═O) CH ₂ NHC (═O ) Phenyl, — (CH ₂ ) _t SO ₂ (alkyl), — (CH ₂ ) _t SO ₂ (phenyl), — (CH ₂ ) _t SO ₂ (thienyl), — (CH ₂ ) _t SO ₂ (imidazolyl) , — (CH ₂ ) _t SO ₂ (furyl), — (CH ₂ ) _t SO ₂ (pyrrolyl), SO ₂ NH (phenyl), —C (═S) NH ₂ , —C (═S) NH (alkyl) ), -C (= S) NH (phenyl), _{(CH 2) C (= O} ) pyrrolidinyl, - _{(CH 2) C (= O} ) piperidyl, - _{(CH 2) C (= O} ) piperazinyl, -CO ₂ (alkyl), - CO ₂ (phenyl), - CO ₂ (benzyl), NHCO ₂ (alkyl), — (CH ₂ ) _t C (═O) NH (phenyl), — (CH ₂ ) _t C (═O) NH (piperidyl), — (CH ₂ ) _t C (═O) NH (thienyl), — (CH ₂ ) _t C (═O) NH (thiazolyl), — (CH ₂ ) _t C (═O) NH (C _5-6 cycloalkyl), — (CH _{2) t C (= O)} NH ( _{benzyl), - (CH 2) t} C (= O) NH ( _{pyrrolidinyl), - (CH 2) t} C (= O) NH ( piperazinyl), - (CH _{2) t C (= O) NH 2} , - (CH 2) t C (= O) NH ( _{alkyl), - (CH 2) t} C (= O) N ( _{alkyl) 2, - (CH 2)} t C ( = O) N _{(C 1 to 4} alkyl) (phenyl), - (CH _{2) t C (= O) N (} C 1~4 alkyl) _{(thienyl), - (CH 2) t} C (= O) N (C 1~4 alkyl) _{(thiazolyl), - (CH 2) t} C (= O) N (C _1-4 alkyl) (benzyl), or — (CH ₂ ) _t C (═O) N (C _1-4 alkyl) CO ₂ (alkyl), wherein each R ₉ Each alkyl, alkenyl or cyclic group is optionally substituted with up to 3 R ₁₈ ;
R ₁₈ is —C _1-4 alkyl, —S (C _1-4 alkyl), C _3-7 cycloalkyl, —SO ₂ (C _1-4 alkyl), —O (C _1-4 alkyl), — SO ₂ -phenyl, halogen, hydroxy, nitro, cyano, — (CH ₂ ) _q CO ₂ H, — (CH ₂ ) _q CO ₂ C _1-4 alkyl, — (CH ₂ ) _q NH ₂ , —O (CH _{2) q CO 2 H, -CH} = CH-CO 2 H, -CH = CH-CO 2 ( _{alkyl), - (CH 2) q} NH ( _{alkyl), - (CH 2) q} NHCO 2 alkyl, - ( C═O) NH—SO ₂ alkyl, — (CH ₂ ) _q NH (benzyl), — (CH ₂ ) _q N (alkyl) ₂ , —O (CH ₂ ) _r N (alkyl) ₂ , —O benzyl, _{-C (= O) (CH 2} ) q NH 2, -C (= O) (CH 2) q NH ( alkyl), - C (= O) (CH 2) q N ( alkyl _{Le) 2, -O (CH 2)} r NH 2, -O (CH 2) r NH ( _{alkyl), - O (CH 2)} r N ( _alkyl) 2, -C (= _O) pyridyl, - (CH _{2) q} phenyl, - (CH _{2) q} pyridyl, - (CH _{2) q} triazolyl, - (CH _{2) q} tetrazolyl, - (CH _{2) q} imidazolyl, - (CH _{2) q} pyrazolyl, - (CH _{2) q} thiamorpholinyl, — (CH ₂ ) _q morpholinyl, — (CH ₂ ) _q thienyl, — (CH ₂ ) _q pyrazinyl, wherein each R ₁₈ alkyl group or cyclic group is optionally 1-2. C _1-4 alkyl, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, —CO ₂ H, CO ₂ C _1-4 alkyl, C _1-4 alkoxy, —S (C _1-4 alkyl), amino and / or amino _{C 1 to 4} alkyl Substituted;
n is 0, 1 or 2;
q is 0, 1, 2, 3 or 4;
r is 1, 2, 3 or 4;
s is 1, 2, 3 or 4; and
t is 0, 1 or 2.

(Production method)
The compounds of the present invention can be prepared by typical reactions described in the following Reaction Schemes AK. Exemplary reagents and methods for these reactions are set forth herein below. Starting materials are commercially available or can be readily prepared by one skilled in the art. In all of the reaction schemes, the groups Z, K, L, Ar, J, T, M, R ₁ , R ₂ , R ₃ , R _4a , R _4b and R _4c are the compounds of formula (I) unless otherwise specified. Are as described herein. The groups generally indicated by R, R ^′ , X and P, as well as the solvent, temperature, pressure, starting material having the desired group, and other reaction conditions are readily selected as appropriate by one skilled in the art. Can do.

適当に官能化したアミノ酸１を、塩基（例えば、ＮａＯＨ、ＫＯＨ、Ｋ_２ＣＯ_３、ＫＨＣＯ_３、Ｎａ_２ＣＯ_３またはＮａＨＣＯ_３）の存在下で水中、イソシナネート２ａまたはイソチオシアネート２ｂと反応させて、酸性化後に、それぞれウレイド酸３ａおよびチオウレイド酸３ｂを得る。次いで、この中間体産物を、有機溶媒または水性溶媒中で、触媒量の酸（例えば、塩酸、硫酸、メタンスルホン酸またはトルエンスルホン酸）の存在下で環化して、式（Ｉｆ）を有するスピロヒダントインまたは式（Ｉｇ）を有するスピロ−２−チオヒダントインを得る（例えば、EspadaらによるFarmaco, 45巻(1990), 1237-1243頁；またはNicoleらによるCan. J. Chem., 40巻(1962), 353-366頁を参照）。別法として、該ウレイド酸またはチオウレイド酸を、有機溶媒（例えば、ＤＭＦ、ＴＨＦ、ＤＣＭ）中、活性化試薬（例えば、ＨＯＢＴまたは１−ヒドロキシ−７−アザベンゾトリアゾール）および非求核性塩基（例えば、ＴＦＡまたはＤＩＰＥＡ）の存在下で、脱水試薬（例えば、ＤＣＣまたはＥＤＣＩ）を用いて環化することができる。

A suitably functionalized amino acid 1 is reacted with isocyaninate 2a or isothiocyanate 2b in water in the presence of a base (eg, NaOH, KOH, K ₂ CO ₃ , KHCO ₃ , Na ₂ CO ₃ or NaHCO ₃ ), After acidification, ureido acid 3a and thioureido acid 3b are obtained, respectively. The intermediate product is then cyclized in an organic or aqueous solvent in the presence of a catalytic amount of an acid (eg, hydrochloric acid, sulfuric acid, methanesulfonic acid or toluenesulfonic acid) to produce a spiro having the formula (If). Hydantoins or spiro-2-thiohydantoins having the formula (Ig) are obtained (for example, Farmaco, 45 (1990), 1237-1243 by Espada et al .; or Can. J. Chem., 40 (1962) by Nicole et al. ), Pages 353-366). Alternatively, the ureido acid or thioureido acid may be combined with an activating reagent (eg HOBT or 1-hydroxy-7-azabenzotriazole) and a non-nucleophilic base (eg, DMF, THF, DCM) For example, it can be cyclized with a dehydrating reagent (eg, DCC or EDCI) in the presence of TFA or DIPEA).

式（Ｉｆ）または（Ｉｇ）を有する化合物はまた、反応式Ｂに示す１個の工程で得ることができる。有機溶媒（例えば、ＴＨＦ、ジクロロメタンまたはＤＭＦ）中、塩基（例えば、ＴＥＡ、Ｋ_２ＣＯ_３またはＫＯＨ）の存在下で、適当に官能化したアミノエステル４をイソシアネート２ａまたはイソチオシアネート２ｂと反応させることにより、それぞれ式（Ｉｆ）または（Ｉｇ）を有する所望する化合物を得る（例えば、ParkらによるJ. Org. Chem., 63巻(1998), 113-117頁；JohnsonらによるJ. Am. Chem. Soc., 40巻(1918), 645頁；およびSchollkopfらによるLiebigs Ann. Chem., (1981), 439-458頁を参照）。

Compounds having formula (If) or (Ig) can also be obtained in one step as shown in Scheme B. Reacting an appropriately functionalized amino ester 4 with an isocyanate 2a or isothiocyanate 2b in the presence of a base (eg TEA, K ₂ CO ₃ or KOH) in an organic solvent (eg THF, dichloromethane or DMF). Yields the desired compound having the formula (If) or (Ig), respectively (eg Park et al., J. Org. Chem., 63 (1998), 113-117; Johnson et al., J. Am. Chem. Soc., 40 (1918), 645; and Schierlkopf et al., Liebigs Ann. Chem., (1981), 439-458).

式（Ｉｆ）のヒダントインを、有機溶媒（例えば、トルエンまたはジオキサン）中、試薬（例えば、Ｐ_２Ｓ_５または２,４−ビス(４−メトキシフェニル)−１,３−ジチア−２,４−ジホスフェタン−２,４−ジスルフィド（ローソン(Lawesson's)試薬）を用いて処理することにより、式（Ｉｆ）を有する対応するジチオヒダントインを得る（例えば、Carringtonらによる、J. Chem. Soc., (1950), 354頁を参照）。

Hydantoin of the formula (If) is reacted with a reagent (eg P ₂ S ₅ or 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4- in an organic solvent (eg toluene or dioxane). Treatment with diphosphetan-2,4-disulfide (Lawesson's reagent) gives the corresponding dithiohydantoins having the formula (If) (see, for example, Carrington et al., J. Chem. Soc., (1950 ), Page 354).

式（Ｉｇ）を有するジチオ−ヒダントインを、反応式Ｄに示す通り、式（Ｉｈ）を有する４−チオ−ヒダントインに変換することができる。式（Ｉｇ）を有する化合物を試薬（例えば、ヨウ化メチル）を用いてＳ−アルキル化し、このものを弱酸性条件下で加水分解して、式（Ｉｈ）を有する４−チオ−ヒダントインを得る（例えば、Carringtonらによる、J. Chem. Soc., 1950, 354を参照）。

Dithio-hydantoin having the formula (Ig) can be converted to 4-thio-hydantoin having the formula (Ih) as shown in Scheme D. A compound having formula (Ig) is S-alkylated using a reagent (eg methyl iodide) and hydrolyzed under mildly acidic conditions to give 4-thio-hydantoin having formula (Ih). (See, for example, Carrington et al., J. Chem. Soc., 1950, 354).

式（Ｉｋ）を有するヒダントインのＮ−アシル化は、有機溶媒（例えば、ＴＨＦまたはアセトニトリル）中、塩基（例えば、ＴＥＡ、ＤＩＰＥＡ、ＤＭＡＰまたはＮａＨ）の存在下で、アシル化剤（例えば、塩化アシル、酸無水物、クロロホルメートまたはイソシアネート）を用いて処理することによって得ることができて、式（ＩＩ）を有するヒダントインを得る（例えば、LinkらによるEur. J. Med. Chem., 19巻(1984), 261-266頁；OrtinらによるAn. R. Soc. Esp. Fis. Quim. Ser. B, (1958), 69頁を参照）。

N-acylation of hydantoins having the formula (Ik) is carried out in the presence of a base (eg TEA, DIPEA, DMAP or NaH) in an organic solvent (eg THF or acetonitrile). , Acid anhydrides, chloroformates or isocyanates) to obtain hydantoins having the formula (II) (see eg Eur. J. Med. Chem., 19 (1984), 261-266; see Ortin et al., An. R. Soc. Esp. Fis. Quim. Ser. B, (1958), p.

式（Ｉｋ）を有するヒダントインのスルホニル化は、塩基（例えば、ＴＥＡ、ＤＩＰＥＡ、ピリジンまたはＤＭＡＰ）の存在下、有機溶媒（例えば、トルエン）中で塩化スルホニルを用いて処理することによって得て、式（Ｉｍ）を有する所望する化合物を得る（例えば、TakayamaらによるAgric. Biol. Chem., 51巻(1987), 1547-1552頁を参照）。

Sulfonylation of hydantoins having the formula (Ik) is obtained by treatment with sulfonyl chloride in an organic solvent (eg toluene) in the presence of a base (eg TEA, DIPEA, pyridine or DMAP) The desired compound having (Im) is obtained (see, eg, Takayama et al., Agric. Biol. Chem., 51 (1987), 1547-1552).

式（Ｉｋ）を有するヒダントインは、非プロトン性溶媒（例えば、ＤＭＦ、ＴＨＦまたはＤＭＳＯ）中で１当量の塩基（例えば、ＮａＨ、ＮａＨＭＤｓ、ＬＤＡ、ＬｉＨＭＤＳ、ＫＨ、ＫＨＭＤＳ、またはｔＢｕＯＫ）を用いて処理し、続いて適当なアルキル化剤（例えば、ヨウ化アルキル、臭化アルキル、塩化アルキル、トシレートまたはメシレート）を加えることによって、Ｎ−アルキル化することができて、式（Ｉｎ）を有するヒダントシンを得る（例えば、ParmeeらによるBioorg. Med. Chem. Lett., 9巻(1999), 749-754頁を参照）。

Hydantoin having formula (Ik) is treated with one equivalent of a base (eg, NaH, NaHMDS, LDA, LiHMDS, KH, KHMDS, or tBuOK) in an aprotic solvent (eg, DMF, THF, or DMSO). Followed by the addition of a suitable alkylating agent (eg, alkyl iodide, alkyl bromide, alkyl chloride, tosylate or mesylate) to allow the hydantocin having the formula (In) to be (See, for example, Parmee et al., Bioorg. Med. Chem. Lett., 9 (1999), pages 749-754).

スピロヒダントインをまた、反応式Ｈに示す通り製造することができる。ヒダントイン６は、有機溶媒（例えば、ＴＨＦ、ＤＭＦ、ＤＭＳＯ）中で２当量の塩基（例えば、ＮａＨ、ＫＨ、ＬｉＨＭＤＳ、ＫＨＭＤＳ、ＬＤＡ、ｔＢｕＯＫ、ＫＯＨ、メチルマグネシウム炭酸、またはＤＢＵ）を用いて連続してまたは直接的にのいずれかで処理して、そして２個の脱離基Ｘ（例えば、Ｃｌ、Ｂｒ、Ｉ、ＯＭｓまたはＯＴｓ）を有する化合物７と反応させて、式（Ｉ）を有する所望するヒダントインを得る（例えば、ColladoらによるTetrahedron Lett., 37巻(1996), 6193-6196頁；FujiwaraらによるJ. Chem. Soc. Perkin Trans. 2, (1980), 1573-1577頁；および、BelzeckiらによるJ. Org. Chem., 45巻(1980) , 2215-2217頁を参照）。

Spirohydantoins can also be prepared as shown in Scheme H. Hydantoin 6 is continuously used in organic solvents (eg, THF, DMF, DMSO) with 2 equivalents of base (eg, NaH, KH, LiHMDS, KHMDS, LDA, tBuOK, KOH, methylmagnesium carbonate, or DBU). Desired having formula (I) by treatment with compound 7 having two leaving groups X (eg Cl, Br, I, OMs or OTs) (Eg, Tetrahedron Lett., 37 (1996), 6193-6196 by Collado et al .; J. Chem. Soc. Perkin Trans. 2, (1980), 1573-1577 by Fujiwara et al .; and Belzecki et al., J. Org. Chem., 45 (1980), 221-2217).

式（Ｉｐ）を有するＮ−非置換ヒダントインは、保護／脱保護の順序を加えた反応式Ｈと同じかまたは類似する方法を用いて製造することができる。従って、ヒダントイン８は、保護基Ｐ（例えば、ＢＯＣ）（例えば、NilssonらによるJ. Med. Chem., 35巻(1992), 3270-3279頁を参照）を用いて窒素上で保護して中間体９を得て、このものを７について上記の通りジアルキル化して、式（Ｉｏ）を有する化合物を得る。脱保護により、式（Ｉｐ）を有する所望するＮ−非置換のスピロヒダントインを得る。

N-unsubstituted hydantoins having the formula (Ip) can be prepared using the same or similar method as Scheme H with the order of protection / deprotection. Thus, hydantoin 8 is protected on nitrogen using a protecting group P (eg, BOC) (see, for example, J. Med. Chem., 35 (1992), 3270-3279 by Nilsson et al.). Obtain body 9, which is dialkylated as described above for 7 to give the compound having formula (Io). Deprotection yields the desired N-unsubstituted spirohydantoin having the formula (Ip).

式（Ｉｑ）を有するブロモスピロヒダントインを、適当な溶媒（例えば、トルエン、ＤＭＦ、ＤＭＥまたは水）中で、パラジウム触媒（例えば、Ｐｄ(ＰＰｈ_３)_４）および塩基（例えば、Ｋ_２ＣＯ_３またはＮａ_２ＣＯ_３）の存在下、通常のスズキカップリング条件下で、芳香族性またはヘテロ芳香族性のボロン酸１０と反応させることによって、式（Ｉｒ）を有するビアリール化合物に変換することができる（例えば、SuzukiらによるSynth. Commun., 11巻(1981), 513頁を参照）。

Bromospirohydantoin having the formula (Iq) is converted into a palladium catalyst (eg Pd (PPh ₃ ) ₄ ) and a base (eg K ₂ CO ₃ or the presence of Na 2 _{CO 3),} in a conventional Suzuki coupling conditions, by reaction with aromatic or heteroaromatic boronic acid 10 can be converted to biaryl compounds having the formula (Ir) (See, e.g., Suzuki et al., Synth. Commun., 11 (1981), 513).

ヒダントイン９を、通常の条件（例えば、還流無水酢酸中での酢酸ナトリウム）下で、芳香族アルデヒド１０を用いるクネーフェナーゲル縮合反応を行なって１１を得ることができ、このものを酸性触媒反応（例えば、トリフルオロ酢酸）下でアミン１２と反応させて、式（ＩＳ）を有するスピロピロロヒダントインを得る。

Hydantoin 9 can be subjected to Kunafener gel condensation reaction using aromatic aldehyde 10 under normal conditions (for example, sodium acetate in refluxing acetic anhydride) to obtain 11, which is converted into an acidic catalytic reaction. Reaction with amine 12 under (e.g. trifluoroacetic acid) provides spiropyrrolohydantoins having the formula (IS).

ヒダントイン（Ｉｔ）を、溶媒（例えば、ＤＣＭまたはＤＣＥ）中で、例えば１−クロロエチルクロロホルメートを用いて脱ベンジル化して、式（Ｉｕ）を有するＮＨ誘導体を得ることができる。式（Ｉｕ）を有する化合物を、温度が室温から還流温度の範囲で、溶媒（例えば、アセトニトリルまたはアセトン）中で、アルキルハライドＲＸ（例えば、ヨウ化アルキル）と反応させることができる。別法として、アルキル化は、溶媒（例えば、アセトニトリルまたはＤＣＥ）中、還元試薬（例えば、トリアセトキシ水素化ホウ素ナトリウムまたはシアノ水素化ホウ素ナトリウム）の存在下でアルデヒドと反応させることによって達成することができて、式（Ｉｖ）の化合物を得る。

Hydantoin (It) can be debenzylated in a solvent (eg, DCM or DCE) using, for example, 1-chloroethyl chloroformate to give an NH derivative having the formula (Iu). A compound having formula (Iu) can be reacted with an alkyl halide RX (eg, alkyl iodide) in a solvent (eg, acetonitrile or acetone) at a temperature ranging from room temperature to reflux temperature. Alternatively, alkylation can be accomplished by reacting with an aldehyde in the presence of a reducing reagent (eg, sodium triacetoxyborohydride or sodium cyanoborohydride) in a solvent (eg, acetonitrile or DCE). To obtain a compound of formula (Iv).

式（Ｉｕ）の化合物をまた、有機塩基（例えば、トリエチルアミンまたはジイソプロピルエチルアミン）または無機塩基（例えば、炭酸ナトリウム）の存在下、溶媒（例えば、ＤＣＭ）中、温度が−１５℃〜室温の範囲でアシルハライド（例えば、塩化アシルまたは臭化アシル）を用いてアシル化することができて、式（Ｉｗ）のアシル化誘導体を得る。化合物（Ｉｗ）はまた、カップリング試薬（例えば、ジシクロヘキシルカルボジイミド）の存在下、溶媒（例えば、ＤＣＭ）中で酸ＲＣＯ_２Ｈと反応させることによって得ることもできる。

Compounds of formula (Iu) may also be reacted in a solvent (eg DCM) in the presence of an organic base (eg triethylamine or diisopropylethylamine) or an inorganic base (eg sodium carbonate) at a temperature ranging from −15 ° C. to room temperature. Acylation with an acyl halide (eg, acyl chloride or bromide) can be used to give an acylated derivative of formula (Iw). Compound (Iw) can also be obtained by reaction with acid RCO ₂ H in a solvent (eg, DCM) in the presence of a coupling reagent (eg, dicyclohexylcarbodiimide).

式（Ｉｘ）のスルホンアミドは、塩基（例えば、トリエチルアミンまたは炭酸ナトリウム）の存在下、溶媒（例えば、ＤＣＭまたはＴＨＦ）中、温度が−１５℃〜室温の範囲でスルホニルハライドと反応させることによって、式（Ｉｕ）の化合物から得ることができる。

The sulfonamide of formula (Ix) is reacted with a sulfonyl halide in the presence of a base (eg triethylamine or sodium carbonate) in a solvent (eg DCM or THF) at a temperature ranging from −15 ° C. to room temperature. It can be obtained from a compound of formula (Iu).

式（Ｉｕ）の化合物はまた、カルボニルジイミダゾールおよびヨウ化メチルとの連続的な反応によって、活性中間体１３に変換することもできる。例えば、R. A. BateyらによるTetrahedron Lett., 39巻(1998), 6267頁を参照。次いで、化合物１３を、アルコールまたはアミンのいずれかと反応させて、それぞれ式（Ｉｙ）のカルバメートまたは式（Ｉｚ）のウレアを得ることができる。

The compound of formula (Iu) can also be converted to the active intermediate 13 by successive reaction with carbonyldiimidazole and methyl iodide. See, for example, Tetrahedron Lett., 39 (1998), 6267 by RA Batey et al. Compound 13 can then be reacted with either an alcohol or an amine to give a carbamate of formula (Iy) or a urea of formula (Iz), respectively.

式（Ｉｕ）の化合物を、溶媒（例えば、ＴＨＦまたはＤＣＭ）中で二炭酸ジｔｅｒｔ−ブチルと反応させることによって、中間体１４に変換することができる。次いで、例えば、酸化ルテニウムの存在下で過ヨウ素酸ナトリウムを用いて１４を酸化することにより、ラクトン１５および１６の混合物を得て、そしてこのものを標準的な条件下で変換して、式（Ｉａａ）および（Ｉｂｂ）の化合物に変換することができる。

A compound of formula (Iu) can be converted to intermediate 14 by reacting with di-tert-butyl dicarbonate in a solvent (eg, THF or DCM). Then, for example, by oxidizing 14 with sodium periodate in the presence of ruthenium oxide, a mixture of lactones 15 and 16 is obtained, which is converted under standard conditions to give the formula ( Can be converted to the compounds of Iaa) and (Ibb).

(Usefulness)
The compounds and compositions of the present invention are antagonists and / or inhibitors of LFA-1, Mac-1 and / or ICAMs. They are useful for treating various inflammatory diseases and disorders relating to the action of LFA-1, Mac-1 and / or ICAMs, particularly LFA-1: ICAM-1. The term “leukocyte integrin / ICAM-related disease” is used herein to relate to the action or level of LFA-1, Mac-1 and / or ICAM-1, ICAM-2 or ICAM-3 for ease of reference. Used to mean a disease or disorder. As used herein, the term “treating” includes prophylactic and therapeutic uses, and as such, this alleviates symptoms of leukocyte integrin / ICAM-related disease in a patient and is associated with the disease. Improvement of identifiable measures to be taken, or prevention of the disease or its symptoms. The term “patient” means a mammal, preferably a human.

  In terms of inhibitory activity, the compounds are used to treat diseases involving activation, co-stimulation or infiltration of T-cells and / or leukocytes (this is in the skin, peritoneum, synovium, lung, kidney and heart). Including but not limited to diseases involving leukocyte influx). The compounds of the present invention can be used to treat diseases resulting from specific or non-specific immune system responses in patients.

  Leukocyte integrin / ICAM-related diseases that can be treated using the compounds of the present invention include acute or chronic versus host graft response (eg, islet allograft); and acute or chronic transplant rejection ( For example, kidney, liver, heart, lung, pancreas, bone marrow, cornea, small intestine, skin allograft, skin allograft, xenograft, and / or cells derived from those organs). In addition, the compounds can be used to treat inflammatory diseases (eg, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, osteoporosis, diabetes (eg, insulin dependent diabetes or juvenile diabetes), Cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, ulcerative colitis, Alzheimer's disease, shock, ankylosing spondylitis, gastritis, conjunctivitis, pancreatitis (acute or chronic), multiple organ injury syndrome ( (Eg secondary to sepsis or trauma), myocardial infarction, atherosclerosis, stroke, reperfusion injury (eg cardiopulmonary or renal dialysis), acute glomerulonephritis, vasculitis, thermal injury (ie sunburn), necrosis Systemic enterocolitis, granulocyte transfusion related syndrome and / or Sjogren's syndrome).

  Inflammatory diseases of the skin using the compounds of the present invention, including eczema, atopic dermatitis, contact dermatitis, urticaria, scleroderma, psoriasis, and skin diseases caused by acute inflammatory components Can be treated.

  Allergic and respiratory diseases with the compounds (including asthma, pulmonary fibrosis, allergic rhinitis, oxygen toxicity, emphysema, chronic bronchitis, acute respiratory distress syndrome and chronic obstructive pulmonary disease (COPD)) Can also be treated. The compounds can be used to treat chronic hepatitis, including hepatitis B and hepatitis C.

  In addition, using the compounds of the present invention, autoimmune diseases and inflammation associated with autoimmune diseases (eg, organ-tissue autoimmune diseases (eg, Raynaud's syndrome), autoimmune thyroiditis, uveitis, systemic lupus, etc.) Lupus erythematosus, Addison's disease, autoimmune multiglandular disease (also known as autoimmune multiglandular syndrome), and Graves' disease) can be treated.

  The compounds of the invention can also be used to treat metastases or as an aid to minimize toxicity from cytokine therapy in the treatment of cancer.

  The compounds of the present invention further have utility in treating hypogonadism, frailty, sexual dysfunction, atrophy (eg, atrophy syndrome associated with cancer and AIDS) and anemia. The compound further treats cancer, including but not limited to breast, brain, skin, ovary, endometrium, bladder, testis, lung, large intestine, lymphatic system, liver and kidney cancer. In particular it has utility. The compounds of the present invention include, for example, hirsutism, acne, seborrhea, alopecia, fibrosis, hyperpilosity, cachexia, polycystic ovary syndrome, anorexia, contraception, withdrawal syndrome, pregnancy arrest and prostate Useful for diseases such as hypertrophy. The compounds are further useful as anti-angiogenic agents. In addition, the compounds may be useful as inhibitors of prenylation of protein prenyltransferases (particularly farnesyltransferase) and oncogene protein Ras. For example, the compounds of the present invention are potentially useful for treating and / or preventing the diseases and disorders cited in WO 01/45704, which forms part of this specification. obtain.

  When used as an anti-inflammatory agent, the compound can be administered before, during or after the onset of inflammation. When used prophylactically, the compound precedes an inflammatory response or symptom (eg, before, at or immediately after organ or tissue transplantation but prior to any symptom of organ rejection) It is preferable to give. Administration of the compound can prevent or attenuate inflammatory reactions or symptoms.

  Accordingly, the present invention provides a method for treating the above mentioned diseases, wherein the method administers an effective amount of at least one compound of formula (I) or a salt thereof to a patient in need of the treatment. Including that. Other therapeutic drugs described below can be used in combination with a compound of formula (I). In the methods of the invention, these other therapeutic drugs can be administered before, simultaneously with, or after administration of the compounds of the invention.

  The present invention also provides pharmaceutical compositions that can treat the above diseases and disorders. The compositions of the present invention can include other therapeutic drugs, which are, for example, according to methods well known in the pharmaceutical formulation art, as usual solid or liquid vehicles or diluents, as well as desired. It can be formulated by using a type of pharmaceutical additive appropriate for the mode of administration (eg, excipients, binders, preservatives, stabilizers, fragrances, etc.).

  The compound of formula (I) can be administered by any method appropriate to the disease to be treated, which may depend on the need for site-specific treatment or the amount of drug being delivered. Although other delivery modes are contemplated, topical administration is usually preferred for skin related diseases and systemic treatment is preferred for cancerous or precancerous diseases. For example, the compound can be administered orally (eg, in the form of tablets, capsules, granules, powders or liquid formulations (including syrups)); topically (eg, solutions, suspensions, Sublingual; buccal; parenteral (eg, subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion (eg, sterile injectable), in the form of a gel or ointment, etc. Aqueous or non-aqueous solutions or suspensions); nasally (eg, by inhalation spray); topically (eg, in the form of a cream or ointment); rectally (eg, suppositories) Or in the form of liposomes. Dosage unit formulations containing non-toxic pharmaceutically acceptable vehicles or diluents can be administered. The compound can be administered in a form suitable for immediate release or extended release. Immediate or delayed release can be achieved using a suitable pharmaceutical composition, or in particular in the case of delayed release, using a device such as a subcutaneous implant or osmotic pump.

  A typical composition for topical administration comprises a topical carrier such as PLASTIBASE® (mineral oil gelled with polyethylene).

  A typical composition for oral administration includes a suspension, which includes, for example, microcrystalline cellulose to provide bulk, alginic acid or sodium alginate as a suspension, methylcellulose as a viscosity enhancer, and Sweeteners or fragrances (eg, those known in the art); immediate release tablets (eg, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose, and / or other Excipients, binders, bulking agents, disintegrants, diluents and lubricants (which may include, for example, those known in the art). The compounds of the invention can also be delivered orally by sublingual and / or buccal administration, eg, using molded, compressed or lyophilized tablets. A typical composition may include a fast dissolving diluent such as mannitol, lactose, and / or cyclodextrin. In these formulations, high molecular weight excipients (eg, cellulose (AVICEL®) or polyethylene glycol (PEG)); excipients that aid in mucosal adhesion (eg, hydroxylpropylcellulose (HPC), hydroxy Propylmethylcellulose (HPMC), sodium carboxymethylcellulose (SCMC) and / or malic anhydride copolymer (eg, GANTREZ®); and drugs for controlling release (eg, polyacrylic acid copolymer) (Eg CARBOPOL 934®)) Lubricants, glidants, fragrances, colorants and stabilizers can also be added for formulation and use convenience. .

  Typical compositions for nasal administration by aerosol or inhalation include solutions, such as benzyl alcohol, other suitable preservatives, absorption enhancers to increase absorption and / or bioavailability, and / Or other solubilizers or dispersants (eg, those known in the art) may be included.

  Typical compositions for parenteral administration include injectable solutions or suspensions, eg, suitable non-toxic parenterally acceptable diluents or solvents (eg, mannitol, 1 , 3-butanediol, water, Ringer's solution, isotonic sodium chloride solution), or other suitable dispersing or wetting agents and suspending agents (these are synthetic mono- or di-glycerides and fatty acids, which are Including oleic acid).

  A typical composition for rectal administration includes a suppository, which may include, for example, a suitable nonirritating excipient such as cocoa butter, a synthetic glyceride ester or polyethylene glycol, Solid at normal temperature, but liquefies and / or dissolves in the rectal cavity to release the drug.

  Effective amounts of the compounds of the present invention can be determined by one of ordinary skill in the art, including typical doses for patients that are 0.05-100 mg / kg body weight of active compound per day, Can be administered in a single dose or in individual doses (eg, 1 to 4 times per day). The particular dose level and number of doses for any particular subject can vary depending on various factors, including the activity of the particular compound used, the metabolic stability and length of action of the compound, the species of the subject , Age, weight, normal health, sex and diet, mode of administration and time, rate of excretion, combination of drugs, disease to be treated, and severity of it) I will. Preferred subjects for treatment include animals, mammals (eg, humans) and domestic animals (eg, dogs, cats, horses, etc.), subjects for leukocyte integrin / ICAM-related diseases, and / or the above diseases and Most preferred are subjects for any of the disorders.

  The compounds and compositions of the present invention may be used alone or in combination with each other and / or other suitable therapeutic drugs useful in treating the above diseases and disorders (eg, is the second drug the same as the parent compound)? Or having a different mechanism of action). These other therapeutic drugs typically include anti-inflammatory drugs, antibiotics, antiviral drugs, antioxidants, and drugs used to treat respiratory diseases (eg, COPD and asthma). Including.

  Examples of suitable other anti-inflammatory agents that can be used with the compounds of the present invention include aspirin, cromolyn, nedocromil, theophylline, zileuton, zafirlukast, montelukast ( montelukast, pranlukast, indomethacin and lipoxygenase inhibitors; non-steroidal anti-inflammatory drugs (NSAIDs) (eg ibuprofen and naproxin); TNF-α inhibitors (eg tenidap and rapamycin or they Derivatives) or TNF-α antagonists (eg, infliximab, Enbrel®, D2E7, OR1384), cytokine modulators (eg, TNF-alpha converting enzyme [TACE] inhibitors, interleukins) Kin-1 converting enzyme (ICE) inhibitors, interleukin-1 receptor antagonists, prednisone, dexamethasone, cyclooxygenase inhibitors (ie, COX-1 and / or COX-2 inhibitors (eg, Naproxen ) (Registered trademark), Celebrex (registered trademark) or Vioxx (registered trademark)), CTLA4-Ig agonist / antagonist (LEA29Y), CD40 ligand antagonist, IMPDH inhibitor (eg, mycophenol) Acids [CellCept (R)] and VX-497), methotrexate (FK506), integrin antagonists (eg, alpha-4beta-1, alpha-V-beta-3), cell adhesion inhibitors, interferon gamma Antagonist Prostaglandin synthesis inhibitor, budesonide, clofazimine, CNI-1493, CD4 antagonist (eg, priliximab), p38 mitogen activated protein kinase inhibitor, protein tyrosine kinase (PTK) inhibitor, IKK inhibitor Therapies for the treatment of irritable bowel syndrome (eg, Zelmac®, Zelnorm® and Maxi-K® openers (eg, US Pat. No. 6,184,231)). B1) or NF-κB inhibitors (eg, calphostin, CSAIDs and quinoxalines (disclosed in US Pat. No. 4,200,750); disassociated steroids; chemokine receptor modulators (This thing CCR1, CCR2, CCR3, CCR4 and CXCR2 receptor antagonists); secreted and cytosolic phospholipase A2 inhibitors, glucocorticoids, salicylic acid, nitric oxide and other immunosuppressive agents; and nuclear translocation inhibitors ( For example, deoxyspergualin (DSG)).

The compounds of the present invention may be used to treat other respiratory diseases (eg, asthma, COPD) and other drugs used to treat allergic rhinitis (eg, β-adrenergic agents (eg, albuterol, terbutaline) , Formoterol, salbutamol, salmeterol, bitolterol, pyrbuterol and fenoterol); corticosteroids such as beclomethasone, triamcinolone, triamclonelone (budesonide), fluticasone, flunisolide, dexamethasone, prednisone and dexamethasone; leukotriene antagonists (eg, Accolate [Zafirlukast (registered trademark) And Singulair [Montelukast®]; muscarinic M3 cholinergic antagonists (eg, Spiriva®), PDE4 inhibitors (eg, rolipram, cilomilast) [Ariflo®, piclamilast or roflumilast, histamine H ₁ antagonist, Allegra® (fexofenadine, Claritin) Trademark (loratidine) and / or Clarinex® (desloratidine) can be used.

  Examples of suitable antiviral agents for use with the compounds of the present invention include nucleoside-based inhibitors, protease-based inhibitors, and viral-assembly inhibitors.

  Examples of anti-osteoporosis agents suitable for use in combination with the compounds of the present invention include alendronate, risedronate, PTH, PTH fragment, raloxifene, calcitonin , RANK ligand antagonists, calcium sensing receptor antagonists, TRAP inhibitors, selective estrogen receptor modulators (SERM) and AP-1 inhibitors.

  Examples of suitable antioxidants for use in combination with the compounds of the present invention include lipid peroxidation inhibitors such as probucol, BO-653, vitamin A, butamine E, AGI-1067 and α-liposome. Acid).

The compounds of the present invention may also contain antidiabetic agents (eg, biguanides (eg, metformin, glucosidase inhibitors (eg, acarbose)), insulin (which can be insulin secretagogues or insulin sensitizers). ), Meglitinide (eg, repaglinide), sulfonylurea (eg, glimepiride, glyburide and glipizide), biguanide / glyburide combinations (eg, glucovance)) Thiozolidinedion (eg, troglitazone,
Rosiglitazone and pioglitazone), PPAR-alpha antagonists, PPAR-gamma agonists, PPAR alpha / gamma dual agonists, SGLT2 inhibitors, fatty acid binding protein (aP2) inhibitors (eg, US Pat. No. 09 No. 519,079 (filed Mar. 6, 2000) and assigned to the present assignee), glucagon-like peptide-1 (GLP-1), glucagon phosphorylase and dipeptidyl peptidase IV (DP4 ) It can also be used in combination with inhibitors.

  In addition, the compounds can be used with drugs that increase cAMP or cGAPf levels in cells for therapeutic benefit. For example, the compounds of the present invention include phosphodiesterase inhibitors (which are PDE1 inhibitors (eg, those described in Journal of Medicinal Chemistry, 40, 2196-2210 [1997]), PDE2 inhibitors, PDE3 inhibitors (eg, Revizinone, pimobendan or olprinone), PDE4 inhibitors (above), PDE7 inhibitors or other PDE inhibitors (eg, dipyridamole, cilostazol, sildenafil, denbutine) ), Theophylline (1,2-dimethylxanthine), ARIFLO® (ie, cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid ), Alofi Phosphorus (arofyline), C-11294A, CDC-801, BAY-19-8004, cipamfylline (SCHam1591), YM-976, PD-189659, mesiopram, pumafentrine, CDC-998, IC When used in combination with -485 and KW-4490).

In terms of their usefulness in treating ischemia, the compounds of the present invention are drugs for inhibiting F ₁ F ₀ -ATPase (which includes efrapeptin, oligomycin, autobell Autovertin B, and compounds described in US patent application Ser. No. 60 / 339,108 (filed Dec. 10, 2001 and assigned to the assignee); alpha- or beta-adrenergic blockers (eg, , Propranolol, nadolol, carvedilol and prazosin), anti-anginal drugs (eg, nitrates (eg, sodium nitrate, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate and nitro vessels) Antiarrhythmic drugs (which are class I drugs (eg propafenone); class II drugs (eg, propranolol); class III drugs (eg, sotalol, dofetilide, amiodarone, azimilide and ibutilide); class IV drugs (eg, dititazem) (ditiazem) and verapamil); K ⁺ channel modulators (eg, _IAch inhibitors, and inhibitors of the K _ν 1 subfamily of K ⁺ channel openers (eg, US application Ser. No. 09 / 729,731 (December 2000)) I _Kur inhibitors, such as the compounds disclosed in the application filed on the 5th))) and gap-junction modulators (eg connexos (I _Kur inhibitors)); anticoagulants or antithrombotic agents (which are aspirin, warfarin) (warfarin), ximelagtran, low molecular weight heparin (eg Lovenox, enoxaparain, and dalteparin), antiplatelet drugs (eg, GPIIb / GPIIIa blockers (eg, abciximab, eptifibatide and tirofiban), thromboxane Receptor antagonists (eg, ifetroban), P2Y ₁ and P2Y ₁₂ antagonists (eg, clopidogrel, ticlopidine, CS-747, and aspirin / clopidogrel combinations), and factor Xa inhibitors (eg, Fondaprinux; and diuretics (eg, sodium-hydrogen exchange inhibitors, chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide) (bendroflumethiazide), methyl chlorothiazide, trichloromethiazide, polythiazide, benzothiazide, triclinafen ethacrylic acid (tricrynafen), chlorthalidone, furosemide, musolimine, bumetanide, triamitren, and triamtene (Including amiloride).

  The compounds of the present invention may also be used in combination with anti-angiogenic agents (eg, compounds that are inhibitors of the VEGF receptor) or with anti-tumor agents (eg, paclitaxel, adriamycin, epithilones, cisplatin and carboplatin). Can be useful together. Examples of anti-cancer and other cytotoxic agents that can be used in combination with the compounds of the present invention include the following: epothilone derivatives (which are described in German Patent No. 4138042.8; WO 97 / 19086, WO 98/22461, WO 98/25929, WO 98/38192, WO 99/01124, WO 99/02224, WO 99/02514, WO 99/03848, WO 99/07692, WO 99/27890, WO 99 / 28324, WO 99/43653, WO 99/54330, WO 99/54318, WO 99/54319, WO 99/65913, WO 99/67252, WO 99/67253 and WO 00/00485); cyclin dependent Sex kinase inhibitors (known in WO 99/24416); and prenyl-protein transferase inhibitors (known in WO 97/30992 and WO 98/54966).

  Combinations of a compound of the present invention and other therapeutic drugs can prove to have additive and synergistic effects. The combination can be advantageous in reducing side effects that can increase the effectiveness of administration or reduce the dose.

  When used in combination with a compound of the present invention, the other therapeutic drugs described above may be, for example, in the amounts indicated in the Doctor's Desk Reference (PDR) or else by those skilled in the art. Can be used in an amount determined by In the methods of the invention, these other therapeutic drugs can be administered before, simultaneously with, or after administration of the compounds of the invention.

  Compounds of formula (I), including the compounds described in the Examples herein, are examined in the assays described below and are measured as inhibitors of LFA-1 and / or ICAM-1 Possible activity levels were shown.

Assay
H1-Hela Adhesion Assay H1-HeLa cells were released from their growth flasks using Versen (Gibco, Grand Island, NY). After centrifugation, the cells are resuspended in growth medium: DMEM (Gibco), 10% fetal calf serum (Hyclone, Logan, UT), 1% Pen-Strep (Gibco) and 1% L-glutamine (Gibco). And were plated for culture at 5,000 cells / well in 96-well plates.

The next day, HSB-2 cells were split at 2 × 10 ⁵ / mL in growth medium: RPMI 1640 (Gibco), 10% FCS, 1% Pen-Strep and 1% L-glutamine. The next day (Day 3), the cells were centrifuged (534 × G) for 8 minutes, washed and resuspended in HBSS at 5 × 10 ⁷ / mL. Calcein-AM, 10 μM (Molecular Probes, Eugene, OR) and 100 nM phorbol myristate acetate (SIGMA, St. Louis, MO) were added to the labeling and activation mixture. After incubating at 37 ° C. for 30 minutes, HBSS (10 mL) was added and the cells were centrifuged as above. The cell pellet was then resuspended and counted.

  While labeling HSB-2 cells, the medium was aspirated from H1-HeLa cells and the plates were washed once with HBSS, followed by the addition of HBSS (50 μL). Then additional HBSS solution containing compound (50 μL), DMSO or anti-CD18 antibody was added to each well. To the H1-HeLa cells, 200,000 HSB-2 cells / well in 100 μL were added followed by incubation for 30 minutes in the dark. The wells were then washed 3 times to remove the unbound cells. The number of bound HSB-2 cells was then measured using a fluorescence plate reader. The percent inhibition by the compound was calculated using vehicle control as 0% inhibition and antibody blocked adhesion as 100% inhibition.

On day 1 of HUVEC adhesion assay , human umbilical vein endothelial cells (HUVEC) (3 passages, Clonetics, San Diego, CA) were grown in T-75 flasks containing EGM bulletkit medium (Clonetics). Set for.

  When HUVEC reached 90% confluence (typically day 4), 96-well plate tissue culture plates were washed with 2.5 μg / mL mouse type IV collagen (Trevigen) diluted in 0.1 M acetic acid (100 μL). / Well). After incubating for at least 3 hours, the collagen was removed and the plates were washed 3 times with HBSS (Gibco). The HUVEC flasks were trypsinized and for use after 4 days the HUVECs were plated at 1250 cells / 200 μL / well onto wells covered with collagen. Twenty hours prior to use, the medium was removed and the cells were stimulated with 10 nM phorbol myristate acetate (PMA, Sigma, St. Louis, MO) (200 μL) in EGM. After the cells reached 90% confluence (typically day 8), the PMA-containing medium was removed, the wells were washed with HBSS, and the HBSS (50 μL) was added to the wells. Then additional solution containing compound (50 μL), DMSO or blocking anti-CD18 was added to each well.

Then, on day 7, HSB-2 cells were washed 2 × 10 ⁵ in RPMI 1640 (Gibco), 10% FCS (Hyclone, Logan, UT), 1% Pen-Strep (Gibco) and 1% L-glutamine (Gibco). / ML. The next day, the cells were centrifuged (534 × G) for 8 minutes, washed and resuspended at 5 × 10 ⁷ / mL in HBSS. For activation and labeling, calcein-AM, 10 μM (Molecular Probes, Eugene, OR) and 100 nM phorbol myristate acetate (Sigma, St. Louis, MO) were added and the cells were incubated at 37 ° C. for 30 minutes. Incubated. After adding HBSS (10 mL), the cells were centrifuged, resuspended and counted.

  HUVEC cells were added with 200,000 labeled and activated HSB-2 cells / well in 100 μL, followed by incubation for 30 minutes in the dark. The wells were washed 3 times with HBSS to remove unbound cells. The number of bound HSB-2 cells was measured using a fluorescence plate reader. The percent inhibition by the compound was calculated using the vehicle control set as 0% inhibition and the antibody blocked adhesion set as 100% inhibition.

(Example)
The following examples illustrate embodiments of the compounds and starting materials of the present invention and are not intended to limit the scope of the claims. The following abbreviations are used herein for ease of reference.
The abbreviation AlCl ₃ is aluminum chloride.
Ac ₂ O is acetic anhydride.
AcONa is sodium acetate.
bp is the boiling point.
CH ₃ CN is acetonitrile.
DCC is dicyclohexylcarbodiimide.
DCE is dichloroethane.
DCM is dichloromethane.
DMAP is 4-dimethylaminopyridine.
DIPEA or DIEA is N, N-diisopropylethylamine.
DME is 1,2-dimethoxyethane.
DMF is dimethylformamide.
EDCI is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.
Et ₂ O is diethyl ether.
HOBT is 1-hydroxybenzotriazole.
EtOAc is ethyl acetate.
EtOH is ethanol.
g is gram.
HCl is hydrochloric acid.
KOH is potassium hydroxide.
K ₂ CO ₃ is potassium carbonate.
L is liters.
LiAlH ₄ is lithium aluminum hydride.
MeCN is acetonitrile.
MeOH is methanol.
MgSO ₄ is magnesium sulfate.
NaH is sodium hydride.
Na ₂ SO ₄ is sodium sulfate.
NaOH is sodium hydroxide.
NMP is 1-methyl-2-pyrrolidinone.
PBr ₃ is phosphorus tribromide.
(Ph ₃ P) ₄ Pd is tetrakis (triphenylphosphine) palladium (0).
PS is polystyrene.
SOCl ₂ is thionyl chloride.
TEA is triethylamine.
mg is milligrams.
mL is milliliters.
μL is microliter.
mmol is mmol.
μmol is micromolar.
mol is mol.
mp is the boiling point.
RT is room temperature.

ＡｌＣｌ_３（１２８．８ｇ、０．９７ｍｏｌ）を、反応フラスコを水浴中で冷却しながら、無水コハク酸（４４．３ｇ、０．４４ｍｏｌ）およびブロモベンゼン（１００ｍＬ、０．９９ｍｏｌ）のＤＣＭ（５００ｍＬ）懸濁液に、２０分以内で数回に分けて加えた。ＲＴで１時間３０分後に、該反応混合物を２時間還流した。冷却後に、該反応媒質を、氷（１．５Ｌ）および濃ＨＣｌ（１００ｍＬ）の混合物中にゆっくりと注いだ。該沈降物を、水で２回、イソプロパノール、そして最後にペンタンで洗浄した。乾燥後に、オフホワイト色固体の４−(４−ブロモフェニル)−４−オキソ酪酸を得た（８６．４ｇ、ｍｐは１４８℃）。¹H NMR (CDCl₃): 7.85 (2H, d, J = 8.5 Hz), 7.62 (2H, d, J = 8.5 Hz), 3.28 (2H, t, J = 6.5 Hz), 2.82 (2H, t, J = 6.5 Hz)。 (Production Example 1)
4- (4-Bromophenyl) -4-oxobutyric acid

AlCl ₃ (128.8 g, 0.97 mol) was added to DCM (500 mL) in succinic anhydride (44.3 g, 0.44 mol) and bromobenzene (100 mL, 0.99 mol) while cooling the reaction flask in a water bath. The suspension was added in several portions within 20 minutes. After 1 hour 30 minutes at RT, the reaction mixture was refluxed for 2 hours. After cooling, the reaction medium was slowly poured into a mixture of ice (1.5 L) and concentrated HCl (100 mL). The precipitate was washed twice with water, isopropanol, and finally with pentane. After drying, an off-white solid 4- (4-bromophenyl) -4-oxobutyric acid was obtained (86.4 g, mp is 148 ° C.). ¹ H NMR (CDCl ₃ ): 7.85 (2H, d, J = 8.5 Hz), 7.62 (2H, d, J = 8.5 Hz), 3.28 (2H, t, J = 6.5 Hz), 2.82 (2H, t, J = 6.5 Hz).

Ｈ_２ＳＯ_４（８６ｍＬ）を含有するＭｅＯＨ（１．７Ｌ）中で、４−(４−ブロモフェニル)−４−オキソ酪酸（８６．４ｇ、０．３３６ｍｍｏｌ）（製造例１）を、２１時間還流した。冷却後に、該淡色沈降物をろ過して除き、そして該反応混合物を乾固するまで濃縮した。得られた固体を水中に入れ、このものをＥｔＯＡｃを用いて２回抽出した。該有機層を希ＮａＯＨで、そしてブラインで２回洗浄し、Ｎａ_２ＳＯ_４を用いて乾燥し、濃縮して、低融点の固体である目的の４−(４−ブロモフェニル)−４−オキソ酪酸メチルエステルを得た（８７．５ｇ、ｍｐは５０℃）。¹H NMR (CDCl₃): 7.85 (2H, d, J = 8.5 Hz), 7.60 (2H, d, J = 8.5 Hz), 3.71 (3H, s), 3.28 (2H, t, J = 6.5 Hz), 2.76 (2H, t, J = 6.5 Hz)。 (Production Example 2)
4- (4-Bromophenyl) -4-oxybutyric acid methyl ester

4- (4-Bromophenyl) -4-oxobutyric acid (86.4 g, 0.336 mmol) (Preparation Example 1) in MeOH (1.7 L) containing H ₂ SO ₄ (86 mL) for 21 hours Refluxed. After cooling, the pale precipitate was filtered off and the reaction mixture was concentrated to dryness. The resulting solid was taken in water and extracted twice with EtOAc. The organic layer is washed twice with dilute NaOH and with brine, dried over Na ₂ SO ₄ , concentrated, and the desired 4- (4-bromophenyl) -4-oxo, a low melting solid. Butyric acid methyl ester was obtained (87.5 g, mp was 50 ° C.). ¹ H NMR (CDCl ₃ ): 7.85 (2H, d, J = 8.5 Hz), 7.60 (2H, d, J = 8.5 Hz), 3.71 (3H, s), 3.28 (2H, t, J = 6.5 Hz) , 2.76 (2H, t, J = 6.5 Hz).

４−(４−ブロモフェニル)−４−オキソ酪酸メチルエステル（１９ｇ、７０ｍｍｏｌ）（製造例２）の無水ジエチルエーテル（１００ｍＬ）溶液を、氷浴を用いて温度を５℃以下に保ちながら、ＬｉＡｌＨ_４（５．３ｇ、１４０ｍｍｏｌ）のエーテル（１００ｍＬ）懸濁液中に滴下した。ＲＴで２時間後に、該反応混合物を４時間還流した。次いで、そのものを５℃まで冷却し、飽和Ｎａ_２ＳＯ_４溶液を用いて温度を１５℃以下に保ちながら加水分解した。該懸濁液をセライトを用いてろ過し、そして濃縮して、黄色油状物（１６．１ｇ）を得て、このものをシリカゲルクロマトグラフィー精製（溶出液：ＤＣＭ／ＭｅＯＨ ９０／１０）を行なって、油状物の１−(４−ブロモフェニル)−ブタン−１,４−ジオール（１５ｇ）を得た。¹H NMR (CDCl₃): 7.40 (2H, d, J = 8.4 Hz), 7.12 (2H, d, J = 8.4 Hz), 4.65 (1H, br s), 4.50-4.60 (1H, m), 3.97 (1H, br s), 3.4-3.65 (2H, m), 1.6-1.85 (2H, m), 1.45-1.6 (2H, m)。 (Production Example 3)
1- (4-Bromophenyl) -butane-1,4-diol

While a solution of 4- (4-bromophenyl) -4-oxobutyric acid methyl ester (19 g, 70 mmol) (Production Example 2) in anhydrous diethyl ether (100 mL) was kept at 5 ° C. or lower using an ice bath, LiAlH ₄ (5.3 g, 140 mmol) in ether (100 mL) suspension. After 2 hours at RT, the reaction mixture was refluxed for 4 hours. Subsequently, it was cooled to 5 ° C. and hydrolyzed using a saturated Na ₂ SO ₄ solution while keeping the temperature at 15 ° C. or lower. The suspension was filtered through celite and concentrated to give a yellow oil (16.1 g) which was purified by silica gel chromatography (eluent: DCM / MeOH 90/10). The oily 1- (4-bromophenyl) -butane-1,4-diol (15 g) was obtained. ¹ H NMR (CDCl ₃ ): 7.40 (2H, d, J = 8.4 Hz), 7.12 (2H, d, J = 8.4 Hz), 4.65 (1H, br s), 4.50-4.60 (1H, m), 3.97 (1H, br s), 3.4-3.65 (2H, m), 1.6-1.85 (2H, m), 1.45-1.6 (2H, m).

ＰＢｒ_３（４ｍＬ、４０ｍｍｏｌ）を、−１０℃に保った１−(４−ブロモフェニル)−ブタン−１,４−ジオール（１５ｇ、６１ｍｍｏｌ）（製造例３）のジエチルエーテル（３００ｍＬ）溶液に１０分間滴下した。ＲＴで２０時間後に、該反応混合物を氷浴を用いて冷却し、そして水（１００ｍＬ）を直ちに加えた。該水相をエーテルを用いて２回抽出した。該有機層を合わせて、希Ｎａ_２ＣＯ_３水溶液で、次いで中性になるまで水で３回洗浄し、硫酸マグネシウムを用いて乾燥し、そして濃縮して、黄色油状物の１−ブロモ−４−(１,４−ジブロモブチル)ベンゼン（１３ｇ）を得た。¹H NMR (CDCl₃): 7.47 (2H, d, J = 8.5 Hz), 7.26 (2H, d, J = 8.5 Hz), 4.8-5.0 (1H, m), 3.42 (2H, t, J = 6.4 Hz), 2.2-2.45 (2H, m), 1.8-2.2 (2H, m)。 (Production Example 4)
1-bromo-4- (1,4-dibromobutyl) benzene

PBr ₃ (4 mL, 40 mmol) was added to a solution of 1- (4-bromophenyl) -butane-1,4-diol (15 g, 61 mmol) (Production Example 3) in diethyl ether (300 mL) kept at −10 ° C. Added dropwise for minutes. After 20 hours at RT, the reaction mixture was cooled using an ice bath and water (100 mL) was added immediately. The aqueous phase was extracted twice with ether. The organic layers were combined, washed with dilute aqueous Na ₂ CO ₃ solution, then 3 times with water until neutral, dried over magnesium sulfate, and concentrated to give a yellow oil of 1-bromo-4 -(1,4-Dibromobutyl) benzene (13 g) was obtained. ¹ H NMR (CDCl ₃ ): 7.47 (2H, d, J = 8.5 Hz), 7.26 (2H, d, J = 8.5 Hz), 4.8-5.0 (1H, m), 3.42 (2H, t, J = 6.4 Hz), 2.2-2.45 (2H, m), 1.8-2.2 (2H, m).

ＡｌＣｌ_３（２３．８ｇ、１７８ｍｍｏｌ）を、ブロモベンゼン（１５５ｍＬ、１．４７ｍｏｌ）に０℃で数回に分けて加えた。３−ブロモプロピオニルクロリド（２５ｇ、１４６ｍｍｏｌ）を、０℃に保った赤色溶液に３０分間かけて滴下した。ＲＴで１時間後に、該反応混合物を５０℃まで１時間かけて加熱した。冷却後に、該混合物を氷／水上に注ぎ、そしてＤＣＭを用いて抽出した。該有機層をＮａ_２ＳＯ_４を用いて乾燥し、そして濃縮して３−ブロモ−１−(４−ブロモフェニル)プロパン−１−オン（３６ｇ）を得て、このものを石油エーテルから結晶化させた（ｍｐは６６℃）。¹H NMR (CDCl₃): 7.82 (2H, d, J = 8.5 Hz), 7.62 (2H, d, J = 8.5 Hz), 3.73 (2H, t, J = 6.5 Hz), 3.55 (2H, t, J = 6.5 Hz)。 (Production Example 5)
3-Bromo-1- (4-bromophenyl) propan-1-one

AlCl ₃ (23.8 g, 178 mmol) was added to bromobenzene (155 mL, 1.47 mol) in several portions at 0 ° C. 3-Bromopropionyl chloride (25 g, 146 mmol) was added dropwise to the red solution maintained at 0 ° C. over 30 minutes. After 1 hour at RT, the reaction mixture was heated to 50 ° C. over 1 hour. After cooling, the mixture was poured onto ice / water and extracted with DCM. The organic layer was dried with Na ₂ SO ₄ and concentrated to give 3-bromo-1- (4-bromophenyl) propan-1-one (36 g), which was crystallized from petroleum ether. (Mp is 66 ° C.). ¹ H NMR (CDCl ₃ ): 7.82 (2H, d, J = 8.5 Hz), 7.62 (2H, d, J = 8.5 Hz), 3.73 (2H, t, J = 6.5 Hz), 3.55 (2H, t, J = 6.5 Hz).

ＮａＢＨ_４（１．５ｇ、３９．７ｍｍｏｌ）を、温度を１０℃以下に保ちながら、３−ブロモ−１−(４−ブロモフェニル)プロパン−１−オン（１１．７ｇ、４０ｍｍｏｌ）（製造例５）のＭｅＯＨ溶液に数回に分けて加えた。ＲＴで１時間後に、１Ｎ塩酸をｐＨが１になるまで５℃で加え、そして該混合物を真空下で濃縮した。該残渣を水中に溶解し、そしてＤＣＭを用いて３回抽出した。該有機層をＮａ_２ＳＯ_４を用いて乾燥し、そして濃縮して、黄色油状物の３−ブロモ−１−(４−ブロモフェニル)プロパン−１−オールを得た（１１．１ｇ）。¹H NMR (CDCl₃): 7.47 (2H, d, J = 8.3 Hz), 7.22 (2H, d, J = 8.3 Hz), 4.87 (1H, br s), 3.50-3.62 (1H, m), 3.31-3.42 (1H, m), 2.35 (1H, OH, br s), 2-2.31 (2H, m)。 (Production Example 6)
3-Bromo-1- (4-bromophenyl) propan-1-ol

NaBH ₄ (1.5 g, 39.7 mmol) was added to 3-bromo-1- (4-bromophenyl) propan-1-one (11.7 g, 40 mmol) while maintaining the temperature at 10 ° C. or lower (Production Example 5). Was added in several portions to the MeOH solution. After 1 h at RT, 1N hydrochloric acid was added at 5 ° C. until the pH was 1, and the mixture was concentrated in vacuo. The residue was dissolved in water and extracted 3 times with DCM. The organic layer was dried with Na ₂ SO ₄ and concentrated to give 3-bromo-1- (4-bromophenyl) propan-1-ol as a yellow oil (11.1 g). ¹ H NMR (CDCl ₃ ): 7.47 (2H, d, J = 8.3 Hz), 7.22 (2H, d, J = 8.3 Hz), 4.87 (1H, br s), 3.50-3.62 (1H, m), 3.31 -3.42 (1H, m), 2.35 (1H, OH, br s), 2-2.31 (2H, m).

ＳＯＣｌ_２（２．８ｍＬ、３８．６ｍｍｏｌ）を、ＤＣＭ（１１０ｍＬ）およびピリジン（３ｍＬ、３７．６ｍｍｏｌ）混合物中の冷却（−２０℃）した３−ブロモ−１−(４−ブロモフェニル)プロパン−１−オール（１１．１ｇ、３７．８ｍｍｏｌ）（製造例６）溶液に滴下した。−２０℃で２時間後に、該反応混合物を氷および１０％ＨＣｌの混合物に注いだ。該有機層を水洗し、Ｎａ_２ＳＯ_４を用いて乾燥し、そして濃縮して黄色油状物（１２．８ｇ）を得た。減圧下で蒸留することにより、無色油状物の１−ブロモ−４−(３−ブロモ−１−クロロプロピル)ベンゼンを得た（５．１ｇ、ｂｐは１２８〜１３０℃／０．５ｍｍＨｇ）。¹H NMR (CDCl₃): 7.4-7.55 (2H, m), 7.15-7.3 (2H, m), 5.07 (1H, m), 3.45-3.6 (1H, m), 3.3-3.45 (1H, m), 2.35-2.65 (2H, m)。 (Production Example 7)
1-Bromo-4- (3-bromo-1-chloropropyl) benzene

SOCl ₂ (2.8 mL, 38.6 mmol) was cooled (−20 ° C.) in a mixture of DCM (110 mL) and pyridine (3 mL, 37.6 mmol) 3-bromo-1- (4-bromophenyl) propane- 1-ol (11.1 g, 37.8 mmol) (Production Example 6) was added dropwise to the solution. After 2 hours at −20 ° C., the reaction mixture was poured onto a mixture of ice and 10% HCl. The organic layer was washed with water, dried over Na ₂ SO ₄ and concentrated to give a yellow oil (12.8 g). Distillation under reduced pressure gave colorless oily 1-bromo-4- (3-bromo-1-chloropropyl) benzene (5.1 g, bp 128-130 ° C./0.5 mmHg). ¹ H NMR (CDCl ₃ ): 7.4-7.55 (2H, m), 7.15-7.3 (2H, m), 5.07 (1H, m), 3.45-3.6 (1H, m), 3.3-3.45 (1H, m) , 2.35-2.65 (2H, m).

３,５−ジクロロフェニルイソチオシアネート（５ｇ、２４．５ｍｍｏｌ）を、ＴＥＡ（７．５ｍＬ、５３．９ｍｍｏｌ）および乾燥ＤＣＭ（４０ｍＬ）の混合物中のエチルグリシネートＨＣｌ塩（３．４ｇ、２４．５ｍｍｏｌ）の懸濁液に、該フラスコを水浴中で冷却しながら数回に分けて加えた。ＲＴで６０時間後に、該溶液を乾固するまで濃縮し、そしてＥｔＯＡｃおよび塩酸の間で分配した。該有機層を水洗し、濃縮した。得られたアモルファス固体をＥｔ_２Ｏで洗浄して、橙色固体の３−(３,５−ジクロロフェニル)−２−チオキソイミダゾリジン−４−オンを得た（５．３ｇ）。¹H NMR (CDCl₃): 7.45 (1H, m), 7.25 (2H, m), 4.44 (2H, s)。 (Production Example 8)
3- (3,5-Dichlorophenyl) -2-thioxoimidazolidin-4-one

3,5-Dichlorophenyl isothiocyanate (5 g, 24.5 mmol) was added to ethyl glycinate HCl salt (3.4 g, 24.5 mmol) in a mixture of TEA (7.5 mL, 53.9 mmol) and dry DCM (40 mL). The flask was added in several portions while the flask was cooled in a water bath. After 60 hours at RT, the solution was concentrated to dryness and partitioned between EtOAc and hydrochloric acid. The organic layer was washed with water and concentrated. The resulting amorphous solid was washed with Et ₂ O to give orange solid 3- (3,5-dichlorophenyl) -2-thioxoimidazolidin-4-one (5.3 g). ¹ H NMR (CDCl ₃ ): 7.45 (1H, m), 7.25 (2H, m), 4.44 (2H, s).

二炭酸ジ−ｔｅｒｔ−ブチル（１．０４ｇ、４．６ｍｍｏｌ）のＭｅＣＮ（１ｍＬ）溶液を、３−(３,５−ジクロロフェニル)−２−チオキソイミダゾリジン−４−オン（１．０４ｇ、４ｍｍｏｌ）（製造例８）およびＤＭＡＰ（７３ｍｇ、０．６ｍｍｏｌ）のＭｅＣＮ（５ｍＬ）懸濁液に加えた。ＲＴで２時間後に、該混合物を蒸発させ、ＥｔＯＡｃに溶かし、ＫＨＳＯ_４水溶液で２回、および水で１回洗浄し、最後に濃縮して、褐色固体の３−(３,５−ジクロロフェニル)−４−オキソ−２−チオキソイミダゾリジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（１．０４ｇ）を得た。¹H NMR (CDCl₃): 7.46 (1H, m), 7.18 (2H, m), 4.54 (2H, s), 1.57 (9H, s)。 (Production Example 9)
3- (3,5-dichlorophenyl) -4-oxo-2-thioxoimidazolidine-1-carboxylic acid tert-butyl ester

A solution of di-tert-butyl dicarbonate (1.04 g, 4.6 mmol) in MeCN (1 mL) was added to 3- (3,5-dichlorophenyl) -2-thioxoimidazolidin-4-one (1.04 g, 4 mmol). ) (Preparation Example 8) and DMAP (73 mg, 0.6 mmol) in MeCN (5 mL) suspension. After 2 hours at RT, the mixture was evaporated, dissolved in EtOAc, washed twice with aqueous KHSO ₄ and once with water, and finally concentrated to a brown solid of 3- (3,5-dichlorophenyl)- 4-Oxo-2-thioxoimidazolidine-1-carboxylic acid tert-butyl ester (1.04 g) was obtained. ¹ H NMR (CDCl ₃ ): 7.46 (1H, m), 7.18 (2H, m), 4.54 (2H, s), 1.57 (9H, s).

１−ブロモ−４−(１,４−ジブロモブチル)ベンゼン（４２３ｍｇ、１．１ｍｍｏｌ）（製造例４）および３−(３,５−ジクロロフェニル)−４−オキソ−２−チオキソイミダゾリジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（３６１ｍｇ、１ｍｍｏｌ）（製造例９）から出発して、実施例１と同じ方法を用いて、白色固体の(５Ｒ^＊,６Ｓ^＊)−６−(４−ブロモフェニル)−３−(３,５−ジクロロフェニル)−４−オキソ−２−チオキソ−１,３−ジアザスピロ[４.４]ノナン−１−カルボン酸ｔｅｒｔ−ブチルエステルを得た（５４ｍｇ）。¹H NMR (CDCl₃): 7.49 (2H, d, J = 8.4 Hz), 7.33 (1H, m), 7.09 (2H, d, J = 8.4 Hz), 6.22 (2H, m), 4.17 (1H, dd, J₁ = 13.2 Hz, J₂ = 5.4 Hz), 2.35-2.6 (3H, m), 2-2.35 (3H, m), 1.69 (9H, s)。 (Production Example 10)
(5R ^* , 6S ^* )-6- (4-Bromophenyl) -3- (3,5-dichlorophenyl) -4-oxo-2-thioxo-1,3-diazaspiro [4.4] nonane-1-carvone Acid tert-butyl ester

1-bromo-4- (1,4-dibromobutyl) benzene (423 mg, 1.1 mmol) (Preparation Example 4) and 3- (3,5-dichlorophenyl) -4-oxo-2-thioxoimidazolidine-1 -Starting from carboxylic acid tert-butyl ester (361 mg, 1 mmol) (Preparation Example 9), using the same method as Example 1, (5R ^* , 6S ^* )-6- (4-bromophenyl) ) -3- (3,5-dichlorophenyl) -4-oxo-2-thioxo-1,3-diazaspiro [4.4] nonane-1-carboxylic acid tert-butyl ester was obtained (54 mg). ¹ H NMR (CDCl ₃ ): 7.49 (2H, d, J = 8.4 Hz), 7.33 (1H, m), 7.09 (2H, d, J = 8.4 Hz), 6.22 (2H, m), 4.17 (1H, dd, J ₁ = 13.2 Hz, J ₂ = 5.4 Hz), 2.35-2.6 (3H, m), 2-2.35 (3H, m), 1.69 (9H, s).

二炭酸ジ−ｔｅｒｔ−ブチル（７．７２ｇ、３５．４ｍｍｏｌ）のＴＨＦ（１００ｍＬ）溶液を、３−(３,５−ジクロロフェニル)−イミダゾリジン−２,４−ジオン（７．５ｇ、３０．６ｍｍｏｌ、このものは上記で引用するFujinamiらの方法に従って製造する）およびＤＭＡＰ（５６０ｍｇ、４．６ｍｍｏｌ）のＴＨＦ（１５０ｍＬ）懸濁液に加えた。ＲＴで３時間後に、該混合物を蒸発させ、ＤＣＭに溶かし、１Ｎ塩酸で２回、およびブラインで１回洗浄し、最後に、白色固体の３−(３,５−ジクロロフェニル)−２,４−ジオキソイミダゾリジン−１−カルボン酸ｔｅｒｔ−ブチルエステルを得た（１０．１７ｇ）。¹H NMR (CDCl₃): 7.40 (1H, m), 7.37 (2H, m), 4.40 (2H, s), 1.58 (9H, s)。 (Production Example 11)
3- (3,5-dichlorophenyl) -2,4-dioxoimidazolidine-1-carboxylic acid tert-butyl ester

A solution of di-tert-butyl dicarbonate (7.72 g, 35.4 mmol) in THF (100 mL) was added to 3- (3,5-dichlorophenyl) -imidazolidine-2,4-dione (7.5 g, 30.6 mmol). This was prepared according to the method of Fujinami et al. Cited above) and DMAP (560 mg, 4.6 mmol) in THF (150 mL) suspension. After 3 hours at RT, the mixture was evaporated, dissolved in DCM, washed twice with 1N hydrochloric acid and once with brine, and finally 3- (3,5-dichlorophenyl) -2,4- Dioxoimidazolidine-1-carboxylic acid tert-butyl ester was obtained (10.17 g). ¹ H NMR (CDCl ₃ ): 7.40 (1H, m), 7.37 (2H, m), 4.40 (2H, s), 1.58 (9H, s).

製造例１および２に記載する方法を用いて、上記の標題化合物を、グルタル酸無水物およびブロモベンゼンから得た。¹H NMR (CDCl₃): 7.83 (2H, d, J = 8.5 Hz), 7.60 (2H, d, J = 8.5 Hz), 3.68 (3H, s), 3.03 (2H, t, J = 7.1 Hz), 2.45 (2H, t, J = 7.1 Hz), 2.06 (2H, m)。 (Production Example 12)
5- (4-Bromophenyl) -5-oxopentanoic acid methyl ester

Using the methods described in Preparation Examples 1 and 2, the above title compound was obtained from glutaric anhydride and bromobenzene. ¹ H NMR (CDCl ₃ ): 7.83 (2H, d, J = 8.5 Hz), 7.60 (2H, d, J = 8.5 Hz), 3.68 (3H, s), 3.03 (2H, t, J = 7.1 Hz) , 2.45 (2H, t, J = 7.1 Hz), 2.06 (2H, m).

製造例３に記載する方法を用いて、５−(４−ブロモフェニル)−５−オキソペンタン酸メチルエステル（製造例１２）（１２．８ｇ、４５ｍｍｏｌ）を、ＬｉＡｌＨ_４（３．４ｇ、９０ｍｍｏｌ）を用いて還元して、黄色油状物の１−(４−ブロモフェニル)−ペンタン−１,５−ジオール（９．４ｇ）を得た。¹H NMR (CDCl₃): 7.42 (2H, d, J = 8.3Hz), 7.15 (2H, d, J = 8.3Hz), 4.56 (1H, m), 3.63 (1H, brs), 3.45-3.6 (2H, m), 2.96 (1H, brs), 1.25-1.9 (6H, m)。 (Production Example 13)
1- (4-Bromophenyl) -pentane-1,5-diol

Using the method described in Preparation Example 3, methyl 5- (4-bromophenyl) -5-oxopentanoic acid (Preparation Example 12) (12.8 g, 45 mmol) was converted to LiAlH ₄ (3.4 g, 90 mmol). To give 1- (4-bromophenyl) -pentane-1,5-diol (9.4 g) as a yellow oil. ¹ H NMR (CDCl ₃ ): 7.42 (2H, d, J = 8.3Hz), 7.15 (2H, d, J = 8.3Hz), 4.56 (1H, m), 3.63 (1H, brs), 3.45-3.6 ( 2H, m), 2.96 (1H, brs), 1.25-1.9 (6H, m).

製造例４に記載する方法を用いて、１−(４−ブロモフェニル)−ペンタン−１,５−ジオール（９．４ｇ、３６．３ｍｍｏｌ）（製造例１３）を、ＰＢｒ_３（３．４ｍＬ、３６．２ｍｍｏｌ）を用いて処理して、黄色油状物の１−ブロモ−４−(１,５−ジブロモペンチル)ベンゼン（６．１ｇ）を得た。¹H NMR (CDCl₃): 7.47 (2H, d, J = 8.5Hz), 7.26 (2H, d, J = 8.5Hz), 4.88 (1H, t, J = 7.5Hz), 3.38 (2H, t, J = 6.6Hz), 2-2.3 (2H, m), 1.8-2.0 (2H, m), 1.55-1.8 (1H, m), 1.4-1.55 (1H, m)。 (Production Example 14)
1-bromo-4- (1,5-dibromopentyl) benzene

Using the method described in Production Example 4, 1- (4-bromophenyl) -pentane-1,5-diol (9.4 g, 36.3 mmol) (Production Example 13) was converted to PBr ₃ (3.4 mL, (36.2 mmol) to give 1-bromo-4- (1,5-dibromopentyl) benzene (6.1 g) as a yellow oil. ¹ H NMR (CDCl ₃ ): 7.47 (2H, d, J = 8.5Hz), 7.26 (2H, d, J = 8.5Hz), 4.88 (1H, t, J = 7.5Hz), 3.38 (2H, t, J = 6.6Hz), 2-2.3 (2H, m), 1.8-2.0 (2H, m), 1.55-1.8 (1H, m), 1.4-1.55 (1H, m).

３−(３,５−ジクロロフェニル)−２,４−ジオキソイミダゾリジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（３．４５ｇ、１０ｍｍｏｌ）（製造例１１）、４−シアノベンズアルデヒド（１．３１ｇ、１０ｍｍｏｌ）およびＮａＯＡｃ（０．８２ｇ、１０ｍｍｏｌ）の混合物を、Ａｃ_２Ｏ（５０ｍＬ）中で３時間還流した。濃縮後に得られた固体を、氷／水およびＤＣＭの混合物中に溶かした。該有機層を乾燥し、そして濃縮して固体（４．４ｇ）を得て、このものをシリカゲルクロマトグラフィー精製（溶出液はＤＣＭを使用）を行なって、白色固体の４−[３−アセチル−１−(３,５−ジクロロフェニル)−２,５−ジオキソイミダゾリジン−４−イリデンメチル]ベンゾニトリル（１．２５ｇ）を得た。ｍｐ＝２１℃。¹H NMR (CDCl₃)：8.52 (1H, s), 7.6-7.75 (4H, m), 7.43 (1H, m), 7.37 (2H, m), 2.78 (3H, s)。 (Production Example 15)
(E) -4- [3-acetyl-1- (3,5-dichlorophenyl) -2,5-dioxoimidazolidine-4-ylidenemethyl] benzonitrile

3- (3,5-dichlorophenyl) -2,4-dioxoimidazolidine-1-carboxylic acid tert-butyl ester (3.45 g, 10 mmol) (Production Example 11), 4-cyanobenzaldehyde (1.31 g, 10 mmol) ) And NaOAc (0.82 g, 10 mmol) was refluxed in Ac ₂ O (50 mL) for 3 h. The solid obtained after concentration was dissolved in a mixture of ice / water and DCM. The organic layer was dried and concentrated to give a solid (4.4 g) which was purified by silica gel chromatography (eluent using DCM) to give 4- [3-acetyl- 1- (3,5-dichlorophenyl) -2,5-dioxoimidazolidine-4-ylidenemethyl] benzonitrile (1.25 g) was obtained. mp = 21 ° C. ¹ H NMR (CDCl ₃ ): 8.52 (1H, s), 7.6-7.75 (4H, m), 7.43 (1H, m), 7.37 (2H, m), 2.78 (3H, s).

製造例１５と同じ方法を用いるが、製造例１１（３４．５ｇ、０．１ｍｍｏｌ）および４−ブロモベンズアルデヒド（１８．５ｇ、０．１ｍｍｏｌ）を用いて、白色固体の上記標題の化合物（１６．８ｇ）を得た。ｍｐ＝２２２℃。¹H NMR (DMSO-d₆)：8.23 (1H, s), 7.79 (1H, m), 7.55-7.75 (6H, m), 2.65 (3H, s)。 Production Example 16
(E) -1-acetyl-5- (4-bromobenzylidene) -3- (3,5-dichlorophenyl) -imidazolidine-2,4-dione

Use the same method as Preparation 15, but use Preparation 11 (34.5 g, 0.1 mmol) and 4-bromobenzaldehyde (18.5 g, 0.1 mmol) to give the above title compound (16. 8 g) was obtained. mp = 222 ° C. ¹ H NMR (DMSO-d ₆ ): 8.23 (1H, s), 7.79 (1H, m), 7.55-7.75 (6H, m), 2.65 (3H, s).

製造例１７は、３つの別方法によって得た：
（１）３−(３,５−ジクロロフェニル)−１−メチル−イミダゾール−２,４−ジオン（７０ｇ、０．２７ｍｏｌ）、４−シアノベンズアルデヒド（５３ｇ、０．４０４ｍｏｌ）およびβ−アラニン（１６．１ｇ、０．１８１ｍｏｌ）の酢酸（１Ｌ）溶液を、３２時間加熱還流した。該溶液を冷却し、そして５０℃で１時間保った。次いで、そのものを３５℃まで冷却し、そして不溶性物質をろ過によって回収して、上記の標題化合物（３５．５ｇ、０．０９５ｍｍｏｌ）を得た。収率は３５％。ｍｐ＝２３６℃。 Production Example 17
(E) -4- [1- (3,5-dichlorophenyl) -3-methyl-2,5-dioxoimidazolidine-4-ylidenemethyl] -benzonitrile

Preparation 17 was obtained by three different methods:
(1) 3- (3,5-dichlorophenyl) -1-methyl-imidazole-2,4-dione (70 g, 0.27 mol), 4-cyanobenzaldehyde (53 g, 0.404 mol) and β-alanine (16. 1 g, 0.181 mol) in acetic acid (1 L) was heated to reflux for 32 hours. The solution was cooled and kept at 50 ° C. for 1 hour. It was then cooled to 35 ° C. and the insoluble material was collected by filtration to give the title compound (35.5 g, 0.095 mmol) as described above. Yield 35%. mp = 236 ° C.

(2) 3- (3,5-dichlorophenyl) -1-methyl-imidazole-2,4-dione (1.3 g, 5 mmol), 4-cyanobenzaldehyde (0.98 g, 7.5 mmol, 1.5 equivalents) , Pyrrolidine (0.3 mL), anhydrous MgSO ₄ (0.9 g, 1.5 eq) and EtOH (35 mL) were heated at 78 ° C. for 18 h. The reaction mixture was filtered hot and the resulting solid was washed with hot EtOH (2 × 20 mL), water (2 × 20 mL), EtOH (2 × 20 mL) and dried. Yield 1.58g.

  (3) 3- (3,5-dichlorophenyl) -1-methyl-imidazole-2,4-dione (1.3 g, 5 mmol), 4-cyanobenzaldehyde (0.98 g, 7.5 mmol, 1.5 equivalents) , A mixture of pyrrolidine (0.3 mL) and EtOH (35 mL) was heated at 78 ° C. for 18 hours. The reaction mixture was filtered hot and the resulting solid was washed with hot EtOH (2 × 20 mL), water (2 × 20 mL), EtOH (2 × 20 mL) and dried. Yield 2.78 g.

４−シアノベンズアルデヒドの代わりに４−ブロモベンズアルデヒドを用いて、製造例１７と同じ方法に従った。¹H NMR (DMSO-d₆)：7.90 (2H, d), 7.72 (1H, m), 7.58 (4H, m), 6.65 (1H, s), 3.24 (3H, s)。 Production Example 18
(E) -5- (4-Bromobenzylidene) -3- (3,5-dichlorophenyl) -1-methyl-imidazolidine-2,4-dione

The same method as in Production Example 17 was followed using 4-bromobenzaldehyde in place of 4-cyanobenzaldehyde. ¹ H NMR (DMSO-d ₆ ): 7.90 (2H, d), 7.72 (1H, m), 7.58 (4H, m), 6.65 (1H, s), 3.24 (3H, s).

ＴＥＡ（７．２ｍＬ、５１ｍｍｏｌ）を、サルコシン(sarcosine)エチルエステルのＨＣｌ塩(３．４ｇ、２４．５ｍｍｏｌ）の乾燥ＤＣＭ（８０ｍＬ）の懸濁液中に加えた。生成したトリエチルアミン塩酸塩をろ過して除き、そしてＤＣＭ（２０ｍＬ）ですすいだ。該ろ液を三ツ口丸底フラスコ中に移し、そしてこのものを５℃まで冷却した。２,６−ジクロロピリジン−４−イルイソシアネート（１０ｇ、５３ｍｍｏｌ）のＤＣＭ（２５ｍＬ）溶液を、内部温度を１０℃以下に保ちながら、１０分間かけて滴下した。ＲＴで９６時間後に、該反応混合物を１０時間還流した。ＲＴまで冷却後に、該溶液をブラインで洗浄し、ＭｇＳＯ_４を用いて乾燥し、そして濃縮した。得られたアモルファス固体をシリカゲルクロマトグラフィー精製（溶出液は、シクロへキサン／ＥｔＯＡｃの８０／２０〜５０／５０を使用する）を行なって、白色固体の上記標題化合物（９．９ｇ）を得た。ｍｐ＝１３４℃。¹H NMR (CDCl₃)：7.75 (2H, s), 4.07 (2H, s), 3.10 (3H, s)。 Production Example 19
3- (2,6-Dichloropyridin-4-yl) -1-methyl-imidazolidine-2,4-dione

TEA (7.2 mL, 51 mmol) was added into a suspension of sarcosine ethyl ester HCl salt (3.4 g, 24.5 mmol) in dry DCM (80 mL). The triethylamine hydrochloride formed was filtered off and rinsed with DCM (20 mL). The filtrate was transferred into a three-necked round bottom flask and cooled to 5 ° C. A solution of 2,6-dichloropyridin-4-yl isocyanate (10 g, 53 mmol) in DCM (25 mL) was added dropwise over 10 minutes keeping the internal temperature below 10 ° C. After 96 hours at RT, the reaction mixture was refluxed for 10 hours. After cooling to RT, the solution was washed with brine, dried with MgSO ₄ and concentrated. The resulting amorphous solid was purified by silica gel chromatography (eluent using 80 / 20-50 / 50 of cyclohexane / EtOAc) to give the title compound (9.9 g) as a white solid. . mp = 134 ° C. ¹ H NMR (CDCl ₃ ): 7.75 (2H, s), 4.07 (2H, s), 3.10 (3H, s).

製造例１７に記載の第３の方法を用いて、製造例１９（５ｇ、１９．２ｍｍｏｌ）を、４−シアノベンズアルデヒド（３．７８ｇ、２８．８ｍｍｏｌ）と反応させて、白色固体の上記標題化合物（５．６ｇ）を得た。ｍｐ＝２３０℃。¹H NMR (CDCl₃)：7.91 (2H, d, J = 8.1 Hz), 7.65-7.75 (4H, m), 6.40 (1H, s), 3.37 (3H, s)。 Example 20
(E) -4- [1- (2,6-Dichloropyridin-4-yl) -3-methyl-2,5-dioxo-imidazolidin-4-ylidenemethyl] benzonitrile

Using the third method described in Preparation Example 17, Preparation Example 19 (5 g, 19.2 mmol) is reacted with 4-cyanobenzaldehyde (3.78 g, 28.8 mmol) to give the above title compound as a white solid. (5.6 g) was obtained. mp = 230 ° C. ¹ H NMR (CDCl ₃ ): 7.91 (2H, d, J = 8.1 Hz), 7.65-7.75 (4H, m), 6.40 (1H, s), 3.37 (3H, s).

上記の標題化合物を、Roussel-Uclaf(1975)によるDE第2548505号およびChem. Abstr., 85巻、46650番に記載の方法に従って製造した。¹H NMR (DMSO-d₆)：8.27 (1H, s), 4.77 (2H, s)。 Production Example 21
2-hydroxymethyl-thiazole-5-carboxylic acid

The above title compound was prepared according to the method described by Roussel-Uclaf (1975) in DE 2548505 and Chem. Abstr., 85, 46650. ¹ H NMR (DMSO-d ₆ ): 8.27 (1H, s), 4.77 (2H, s).

粗製造例２１（３００ｍｇ、１．９ｍｍｏｌ）および濃硫酸（２ｍＬ）のＥｔＯＨ（３０ｍＬ）溶液を、５時間還流した。該溶媒を減圧下で濃縮し、そして該残渣をＮａ_２ＣＯ_３水溶液およびＥｔＯＡｃの間で分配した。有機相を水洗し、硫酸ナトリウムで乾燥し、そして減圧下で濃縮して、褐色油状物（３２０ｍｇ、１．７ｍｍｏｌ）を得た。¹H NMR (CDCl₃)：8.28 (1H, s); 4.94 (2H, s); 4.33 (2H, q); 1.35 (3H, t)。 Production Example 22
2-hydroxymethyl-thiazole-5-carboxylate ethyl

A solution of crude preparation 21 (300 mg, 1.9 mmol) and concentrated sulfuric acid (2 mL) in EtOH (30 mL) was refluxed for 5 hours. The solvent was concentrated under reduced pressure and the residue was partitioned between aqueous Na ₂ CO ₃ and EtOAc. The organic phase was washed with water, dried over sodium sulfate and concentrated under reduced pressure to give a brown oil (320 mg, 1.7 mmol). _{^{1 H NMR (CDCl 3):}} 8.28 (1H, s); 4.94 (2H, s); 4.33 (2H, q); 1.35 (3H, t).

２−メチルチアゾール−４−カルボン酸エチル（５００ｍｇ、２．９ｍｍｏｌ）、Ｎ−ブロモスクシンイミド（８７７ｍｇ、４．９ｍｍｏｌ）および過酸化ベンゾイル（５〜１０ｍｇ）の１,２−ＤＣＥ（３ｍＬ）混合物を、７０℃で８５時間加熱した。室温まで冷却後に、ＤＣＭ（１０ｍＬ）を加え、そして水洗（３回）した。該有機層をＮａ_２ＳＯ_４で乾燥し、そして真空下で蒸発させた。該残渣をプレパラティブクロマトグラフィーによって精製して、上記標題化合物（５８ｍｇ）を得た。¹H NMR (CDCl₃)：8.23 (1H, s), 4.77 (2H, s), 4.43 (2H, q), 1.42 (3H, t)。 Production Example 23
2-Bromomethylthiazole-4-carboxylate ethyl

1,2-DCE (3 mL) mixture of ethyl 2-methylthiazole-4-carboxylate (500 mg, 2.9 mmol), N-bromosuccinimide (877 mg, 4.9 mmol) and benzoyl peroxide (5-10 mg) Heated at 70 ° C. for 85 hours. After cooling to room temperature, DCM (10 mL) was added and washed with water (3 times). The organic layer was dried over Na ₂ SO ₄ and evaporated under vacuum. The residue was purified by preparative chromatography to give the title compound (58 mg). ¹ H NMR (CDCl ₃ ): 8.23 (1H, s), 4.77 (2H, s), 4.43 (2H, q), 1.42 (3H, t).

上記標題化合物を、Heterocycles, 23巻, 3 (1985), 571-585頁に記載の方法に従って製造した。¹H NMR (CDCl₃)：6.74 (1H, s), 4.50 (2H, q), 1.42 (3H, t)。 Production Example 24
5-Bromomethylisoxazole-3-carboxylate ethyl

The above title compound was prepared according to the method described in Heterocycles, Vol. 23, 3 (1985), pages 571-585. ¹ H NMR (CDCl ₃ ): 6.74 (1H, s), 4.50 (2H, q), 1.42 (3H, t).

実施例１５（３７３．５ｍｇ、０．９ｍｍｏｌ）のＴＨＦ（７ｍＬ）溶液に、ＴＥＡ（１７５μＬ、１．２６ｍｍｏｌ）およびブロモアセチルブロミド（９４μＬ、１．０８ｍｍｏｌ）を加えた。ＲＴで１５分後に、該反応混合物を乾固するまで蒸発させた。該残渣をＤＣＭ（２０ｍＬ）および１Ｎ ＨＣｌ溶液（１０ｍＬ）の間で分配した。該ＤＣＭ層をブラインで洗浄し、硫酸ナトリウムで乾燥し、そして濃縮して粗化合物（４４１．３ｍｇ）を得た。¹H NMR (CDCl₃)：7.75 (2H, d), 7.45-7.55 (3H, m), 6.7-6.9 (2H, m), 4.55-3.65 (7H, m), 3.25 (3H, m)。 Production Example 25
4-[(5S ^* , 9R ^* )-7-bromoacetyl) -3- (3,5-dichloro-phenyl) -1-methyl-2,4-dioxo-1,3,7-triaza-spiro [4 .4] Nona-9-yl] benzonitrile

To a solution of Example 15 (373.5 mg, 0.9 mmol) in THF (7 mL) was added TEA (175 μL, 1.26 mmol) and bromoacetyl bromide (94 μL, 1.08 mmol). After 15 minutes at RT, the reaction mixture was evaporated to dryness. The residue was partitioned between DCM (20 mL) and 1N HCl solution (10 mL). The DCM layer was washed with brine, dried over sodium sulfate and concentrated to give the crude compound (441.3 mg). ¹ H NMR (CDCl ₃ ): 7.75 (2H, d), 7.45-7.55 (3H, m), 6.7-6.9 (2H, m), 4.55-3.65 (7H, m), 3.25 (3H, m).

トリフルオロメタンスルホン酸無水物（１．０４ｍＬ、６．２ｍｍｏｌ）を、冷却した（５℃）４−ヒドロキシ安息香酸ｔｅｒｔ−ブチル（１ｇ、５．１ｍｍｏｌ）のＤＣＭ（２５ｍＬ）とＴＥＡ（１．１ｍＬ、７．８ｍｍｏｌ）混合物の溶液に加えた。５℃で４時間後に、水を加えた。該有機層を分離し、ＭｇＳＯ_４で乾燥し、そして真空下で濃縮した。該残渣をシリカゲルクロマトグラフィー精製（溶出液は、シクロヘキサン／ｉＰｒ_２Ｏの９５／５である）を行なって、無色油状物の上記標題化合物（１．４５ｇ）を得た。¹H NMR (CDCl₃)：8.09 (2H, d, J = 8.6 Hz), 7.32 (2H, d, J = 8.6 Hz), 1.60 (9H, s)。 Production Example 26
4-trifluoromethanesulfonyloxy-benzoic acid tert-butyl ester

Trifluoromethanesulfonic anhydride (1.04 mL, 6.2 mmol) was cooled (5 ° C.) tert-butyl 4-hydroxybenzoate (1 g, 5.1 mmol) in DCM (25 mL) and TEA (1.1 mL, 7.8 mmol) to the mixture solution. After 4 hours at 5 ° C., water was added. The organic layer was separated, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent is 95/5 of cyclohexane / iPr ₂ O) to give the title compound (1.45 g) as a colorless oil. ¹ H NMR (CDCl ₃ ): 8.09 (2H, d, J = 8.6 Hz), 7.32 (2H, d, J = 8.6 Hz), 1.60 (9H, s).

実施例１５（３００ｍｇ、０．７２ｍｍｏｌ）、Ｃｓ_２ＣＯ_３（３３０ｍｇ、１ｍｍｏｌ）、ラセミＢＩＮＡＰ（３３．７ｍｇ、０．０５ｍｍｏｌ）、Ｐｄ(ＯＡｃ)_２（８．１ｍｇ、０．０３６ｍｍｏｌ）および製造例２６（２８３ｍｇ、０．８７ｍｍｏｌ）の混合物を、ジオキサン（５ｍＬ）中、８０℃で２４時間加熱した。室温まで冷却後に、該不溶性塩を除去した。該ろ液を真空下で濃縮して、そしてこのものをシリカゲルクロマトグラフィー（溶出液はＤＣＭである）を用いて精製して、上記標題化合物（１３９ｍｇ）を得た。¹H NMR (CDCl₃)：7.94 (2H, d, J = 8.5 Hz), 7.69 (2H, d, J = 8.1 Hz), 7.40 (2H, d, J = 8.1 Hz), 6.63 (2H, d, J = 8.5 Hz), 3.7-4.2 (6H, m), 3.26 (3H, s), 1.59 (9H, s)。 Production Example 27
4-[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4. 4] Nona-7-yl] benzoic acid tert-butyl ester

Example _{15 (300mg, 0.72mmol), Cs} 2 CO 3 (330mg, 1mmol), racemic BINAP (33.7mg, 0.05mmol), Pd (OAc) 2 (8.1mg, 0.036mmol) and Preparation A mixture of 26 (283 mg, 0.87 mmol) was heated in dioxane (5 mL) at 80 ° C. for 24 hours. After cooling to room temperature, the insoluble salt was removed. The filtrate was concentrated in vacuo and purified using silica gel chromatography (eluent is DCM) to give the title compound (139 mg). ¹ H NMR (CDCl ₃ ): 7.94 (2H, d, J = 8.5 Hz), 7.69 (2H, d, J = 8.1 Hz), 7.40 (2H, d, J = 8.1 Hz), 6.63 (2H, d, J = 8.5 Hz), 3.7-4.2 (6H, m), 3.26 (3H, s), 1.59 (9H, s).

トリフェニルメチルクロリド（３４８ｍｇ。１．２５ｍｍｏｌ）のＤＣＭ（２ｍＬ）溶液を、５−(２−メチルフェニル)−１Ｈ−テトラゾール（２００．５ｍｇ、１．２５ｍｍｏｌ）およびＴＥＡ（１７４μＬ、１．２５ｍｍｏｌ）のＤＣＭ（８ｍＬ）混合物に滴下した。該反応混合物をＲＴで終夜撹拌し、次いでこのものを水洗（１０ｍＬ）した。該有機層を硫酸ナトリウムを用いて乾燥し、そして真空下で濃縮した。該残渣をプレパラティブクロマトグラフィー（シクロヘキサン／ＥｔＯＡｃの９５：５を使用）によって精製して、上記標題化合物（１５９ｍｇ）を得た。¹H NMR (CDCl₃)：8.1 (1H, d), 7.45-7.1 (18H, m), 2.5 (3H, s)。 Production Example 28
5-o-Tolyl-1-trityl-1H-tetrazole

A solution of triphenylmethyl chloride (348 mg. 1.25 mmol) in DCM (2 mL) was added 5- (2-methylphenyl) -1H-tetrazole (200.5 mg, 1.25 mmol) and TEA (174 μL, 1.25 mmol). Added dropwise to a mixture of DCM (8 mL). The reaction mixture was stirred at RT overnight, then it was washed with water (10 mL). The organic layer was dried using sodium sulfate and concentrated under vacuum. The residue was purified by preparative chromatography (using cyclohexane / EtOAc 95: 5) to give the title compound (159 mg). ¹ H NMR (CDCl ₃ ): 8.1 (1H, d), 7.45-7.1 (18H, m), 2.5 (3H, s).

製造例２８（９６．９ｍｇ、０．２４ｍｍｏｌ）、Ｎ−ブロモスクシンイミド（４２．７ｍｇ、０．２４ｍｍｏｌ）および過酸化ベンゾイル（５．８ｇ、０．０２４ｍｍｏｌ）の１,２−ジクロロメタン（５ｍＬ）混合物を、窒素下で７時間還流した。真空で蒸発後に該粗標題化合物を得て、このものを更に精製することなく使用した。¹H NMR (CDCl₃)：8.15 (1H, m), 7.45-7.1 (18H, m), 4.9 (2H, s)。 Production Example 29
5- (2-Bromomethyl-phenyl) -1-trityl-1H-tetrazole

A mixture of Preparation Example 28 (96.9 mg, 0.24 mmol), N-bromosuccinimide (42.7 mg, 0.24 mmol) and benzoyl peroxide (5.8 g, 0.024 mmol) in 1,2-dichloromethane (5 mL). Reflux under nitrogen for 7 hours. The crude title compound was obtained after evaporation in vacuo and used without further purification. ¹ H NMR (CDCl ₃ ): 8.15 (1H, m), 7.45-7.1 (18H, m), 4.9 (2H, s).

上記の標題化合物を、文献（Y. LangloisおよびP. Potierによる、Tetrahedron, 31巻 (1975), 419-422頁を参照）に記載する方法に従って製造した。¹H NMR (DMSO-d₆)：8.98 (1H, s), 8.30 (2H,d), 7.63 (2H,d), 5.64 (1H, t), 4.64 (2H, d), 3.88 (3H, 1H)。 Production Example 30
6-hydroxymethyl-nicotinic acid methyl ester

The above title compound was prepared according to the method described in the literature (see Y. Langlois and P. Potier, Tetrahedron , 31 (1975), pages 419-422). ¹ H NMR (DMSO-d ₆ ): 8.98 (1H, s), 8.30 (2H, d), 7.63 (2H, d), 5.64 (1H, t), 4.64 (2H, d), 3.88 (3H, 1H ).

三臭化リン（１．４ｇ、５．３２ｍｍｏｌ）を、トルエン（１００ｍＬ）中の製造例３０（１ｇ、５．７ｍｍｏｌ）の冷（氷／水／塩化ナトリウム浴）溶液にゆっくりと加えた。該反応混合物をＲＴまで終夜昇温させ、次いでこのものを１時間還流した。該反応混合物をＲＴまで冷却し、そしてＤＣＭを加えた。該有機層を飽和炭酸水素ナトリウム水溶液で、次いで水で洗浄し、硫酸ナトリウムで乾燥し、そして減圧下で濃縮して、油状物（ｍ＝０．９９ｇ、収率は７６％）を得て、このものを更に精製することなく使用した。¹H NMR (CDCl₃)：9.18 (1H, s); 8.35 (1H, d); 7.56 (1H, d); 4.62 (2H, s); 4.00 (3H,s)。 Production Example 31
6-Bromomethyl-nicotinic acid methyl ester

Phosphorus tribromide (1.4 g, 5.32 mmol) was slowly added to a cold (ice / water / sodium chloride bath) solution of Preparation 30 (1 g, 5.7 mmol) in toluene (100 mL). The reaction mixture was allowed to warm to RT overnight and then it was refluxed for 1 hour. The reaction mixture was cooled to RT and DCM was added. The organic layer was washed with saturated aqueous sodium bicarbonate solution, then with water, dried over sodium sulfate, and concentrated under reduced pressure to give an oil (m = 0.99 g, yield 76%), This was used without further purification. ¹ H NMR (CDCl ₃ ): 9.18 (1H, s); 8.35 (1H, d); 7.56 (1H, d); 4.62 (2H, s); 4.00 (3H, s).

アジドナトリウム（２．９ｇ、４４．６ｍｍｏｌ）およびＴＥＡ塩酸塩（４．１３ｇ、３０ｍｍｏｌ）を、５−ホルミル−チオフェン−３−カルボニトリル（２ｇ、１５ｍｍｏｌ、このものは国際出願ＷＯ０２／２６７１８号に従って製造する）のＤＭＦ（５０ｍＬ）溶液に加えた。該溶液を１２時間還流した。ＲＴまで冷却後に、水を加え、そして該溶液をＨＣｌを用いて注意深く酸性とした。該溶液をＥｔＯＡｃを用いて３回抽出した。該有機層を合わせて、Ｎａ_２ＳＯ_４で乾燥し、そして減圧下で濃縮して、褐色固体の目的物（５４０ｍｇ）を得て、このものを更に精製することなく使用した。 Production Example 32
4- (1H-tetrazol-5-yl) -thiophene-2-carboxaldehyde

Sodium azide (2.9 g, 44.6 mmol) and TEA hydrochloride (4.13 g, 30 mmol) were prepared according to the international application WO 02/26718, 5-formyl-thiophene-3-carbonitrile (2 g, 15 mmol). Was added to a DMF (50 mL) solution. The solution was refluxed for 12 hours. After cooling to RT, water was added and the solution was carefully acidified with HCl. The solution was extracted 3 times with EtOAc. The organic layers were combined, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the desired product (540 mg) as a brown solid that was used without further purification.

ＫＯＨ薄片（１．３ｇ、２３．２ｍｍｏｌ）を、ＲＴで１−ブロモ−４−(１,４−ジブロモブチル)ベンゼン（４．０８ｇ、１０．６ｍｍｏｌ）（製造例４）および３−(３,５−ジクロロフェニル)−１−メチルイミダゾリジン−２,４−ジオン（２．５ｇ、９．６ｍｍｏｌ、このものは上記で引用するFujinamiらによる方法に従って製造する）の乾燥ＤＭＳＯ（４０ｍＬ）溶液に加えた。ＲＴで３０時間後に、該反応混合物を水に注ぎ、そしてＥｔＯＡｃを用いて抽出した。該有機層をＮａ_２ＳＯ_４を用いて乾燥し、そして濃縮して、橙色油状物（４．９８ｇ）を得て、このものをシリカゲルクロマトグラフィー（ＤＣＭ／ペンタンの５０／５０）精製を行なって、上に示す相対的な立体化学を有する白色固体の６−(４−ブロモフェニル)−３−(３,５−ジクロロフェニル)−１−メチル−１,３−ジアザスピロ[４.４]ノナン−２,４−ジオン（２．１ｇ）を得た。¹H NMR (CDCl₃)：7.45 (2H, d, J = 8.4 Hz), 7.25 (1H, m), 7.03 (2H, d, J = 8.4 Hz), 6.65 (2H, m), 3.36 (1H, dd, J₁ = 12.9 Hz, J₂ = 6.2 Hz), 3.13 (3H, s), 2.4-2.65 (1H, m), 1.8-2.4 (5H, m)。 Example 1
(5R ^* , 6S ^* )-6- (4-Bromophenyl) -3- (3,5-dichlorophenyl) -1-methyl-1,3-diazaspiro [4.4] nonane-2,4-dione

KOH flakes (1.3 g, 23.2 mmol) were added at RT to 1-bromo-4- (1,4-dibromobutyl) benzene (4.08 g, 10.6 mmol) (Preparation Example 4) and 3- (3, 5-Dichlorophenyl) -1-methylimidazolidine-2,4-dione (2.5 g, 9.6 mmol, which is prepared according to the method by Fujinami et al., Cited above) was added to a dry DMSO (40 mL) solution. . After 30 hours at RT, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried using Na ₂ SO ₄ and concentrated to give an orange oil (4.98 g) which was purified by silica gel chromatography (DCM / pentane 50/50). White solid 6- (4-bromophenyl) -3- (3,5-dichlorophenyl) -1-methyl-1,3-diazaspiro [4.4] nonane-2 having the relative stereochemistry shown above , 4-dione (2.1 g) was obtained. ¹ H NMR (CDCl ₃ ): 7.45 (2H, d, J = 8.4 Hz), 7.25 (1H, m), 7.03 (2H, d, J = 8.4 Hz), 6.65 (2H, m), 3.36 (1H, dd, J ₁ = 12.9 Hz, J ₂ = 6.2 Hz), 3.13 (3H, s), 2.4-2.65 (1H, m), 1.8-2.4 (5H, m).

１−ブロモ−４−(３−ブロモ−１−クロロプロピル)ベンゼン（製造例７）および３−(３,５−ジクロロフェニル)−１−メチルイミダゾリジン−２,４−ジオンから出発して、実施例１と同じ方法を用いて、逆相ＨＰＬＣ精製（ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの５／９５／０．０５〜ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの８０／２０／０．０５の勾配を使用）後に、上記標題化合物を得た。¹H NMR (CDCl₃): 7.44 (2H, d, J = 8.4 Hz), 7.25 (1H, m), 6.95-7 (4H, m), 4.05 (1H, t, J = 10.1 Hz), 3.22 (3H, s), 2.65-2.85 (1H, br q), 2.4-2.65 (2H, m), 2.1-2.3 (1H, br q)。 Example 2
(1S ^* , 4R ^* )-1- (4-Bromophenyl) -7- (3,5-dichlorophenyl) -5-methyl-5,7-diazaspiro [3.4] octane-6,8-dione

Performed starting from 1-bromo-4- (3-bromo-1-chloropropyl) benzene (Preparation Example 7) and 3- (3,5-dichlorophenyl) -1-methylimidazolidine-2,4-dione using the same method as example 1, a reverse-phase HPLC purification _{(CH 3 CN / H 2 O} / TFA for _{5/95 / 0.05~CH 3 CN /} H 2 of O / TFA 80/20 / 0.05 The title compound was obtained after using a gradient. ¹ H NMR (CDCl ₃ ): 7.44 (2H, d, J = 8.4 Hz), 7.25 (1H, m), 6.95-7 (4H, m), 4.05 (1H, t, J = 10.1 Hz), 3.22 ( 3H, s), 2.65-2.85 (1H, br q), 2.4-2.65 (2H, m), 2.1-2.3 (1H, br q).

１−ブロモ−４−(１,５−ジブロモペンチル)ベンゼン（４．２ｇ、１０．９ｍｍｏｌ）（製造例１４）および３−(３,５−ジクロロフェニル)−１−メチルイミダゾリジン−２,４−ジオン（２５９ｇ、１０ｍｍｏｌ）から出発して、実施例１と同じ方法を用いて、白色固体の上記標題化合物（３．１ｇ、ｍｐ＝１１８℃）を得た。¹H NMR (CDCl₃)：7.41 (2H, d, J = 8.4 Hz), 7.30 (1H, m), 7.00 (2H, d, J = 8.4 Hz), 6.90 (2H, m), 3.03 (3H, s), 2.91 (1H, dd, J₁ = 12.9 Hz, J₂ = 3.6 Hz), 2.55 (1H, dq), 2.1-2.3 (1H, m), 1.8-2.05 (5H, m), 1.3-1.6 (1H, m)。 Example 3
(5R ^* , 6S ^* )-6- (4-Bromophenyl) -3- (3,5-dichlorophenyl) -1-methyl-1,3-diazaspiro [4.5] decane-2,4-dione

1-bromo-4- (1,5-dibromopentyl) benzene (4.2 g, 10.9 mmol) (Preparation Example 14) and 3- (3,5-dichlorophenyl) -1-methylimidazolidine-2,4- Using the same method as Example 1 starting from dione (259 g, 10 mmol), the above title compound (3.1 g, mp = 118 ° C.) was obtained as a white solid. ¹ H NMR (CDCl ₃ ): 7.41 (2H, d, J = 8.4 Hz), 7.30 (1H, m), 7.00 (2H, d, J = 8.4 Hz), 6.90 (2H, m), 3.03 (3H, s), 2.91 (1H, dd, J ₁ = 12.9 Hz, J ₂ = 3.6 Hz), 2.55 (1H, dq), 2.1-2.3 (1H, m), 1.8-2.05 (5H, m), 1.3-1.6 (1H, m).

１−ブロモ−４−(１,４−ジブロモブチル)ベンゼン（１５３ｍｇ、０．４ｍｍｏｌ）（製造例４）および３−(３,５−ジクロロフェニル)−２,４−ジオキソイミダゾリジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（１１３ｍｇ、０．３３ｍｍｏｌ）（製造例１１）から出発して、実施例１と同じ方法を用いて、白色固体の上記標題化合物（３３ｍｇ）を得た。¹H NMR (CDCl₃): 7.48 (2H, d, J = 8.3 Hz), 7.30 (1H, m), 7.07 (2H, d, J = 8.3 Hz ), 6.52 (2H, m), 4.06 (1H, dd, J₁ = 13.1 Hz, J₂ = 5.5 Hz), 2.35-2.6 (3H, m), 2-2.35 (3H, m), 1.66 (9H, s)。 Example 4
(5R ^* , 6S ^* )-6- (4-Bromophenyl) -3- (3,5-dichlorophenyl) -2,4-dioxo-1,3-diazaspiro [4.4] nonane-1-carboxylic acid tert -Butyl ester

1-Bromo-4- (1,4-dibromobutyl) benzene (153 mg, 0.4 mmol) (Preparation Example 4) and 3- (3,5-dichlorophenyl) -2,4-dioxoimidazolidine-1-carvone Using the same method as in Example 1, starting from the acid tert-butyl ester (113 mg, 0.33 mmol) (Preparation Example 11), the title compound (33 mg) as a white solid was obtained. ¹ H NMR (CDCl ₃ ): 7.48 (2H, d, J = 8.3 Hz), 7.30 (1H, m), 7.07 (2H, d, J = 8.3 Hz), 6.52 (2H, m), 4.06 (1H, dd, J ₁ = 13.1 Hz, J ₂ = 5.5 Hz), 2.35-2.6 (3H, m), 2-2.35 (3H, m), 1.66 (9H, s).

６−(４−ブロモフェニル)−３−(３,５−ジクロロフェニル)−４−オキソ−２−チオキソ−１,３−ジアザスピロ[４.４]ノナン−１−カルボン酸ｔｅｒｔ−ブチルエステル（４２ｍｇ、７４μｍｏｌ）（製造例１０）を、ＲＴでＴＦＡ／ＤＣＭ／Ｈ_２Ｏ（１／１／０.１）溶液（１ｍＬ）に加えた。３０分後に、該反応混合物を濃縮してベージュ色固体を得て、このものをペンタンで洗浄して、６−(４−ブロモフェニル)−３−(３,５−ジクロロフェニル)−２−チオキソ−１,３−ジアザスピロ[４.４]ノナン−４−オン（２１ｍｇ、ベージュ色固体）を得た。¹H NMR (CDCl₃)：8.39 (1H, s), 7.51 (2H, d, J = 8.4 Hz), 7.35 (1H, m), 7.19 (2H, d, J = 8.4 Hz ), 6.44 (2H, m), 3.36 (1H, dd, J₁ = 12.9 Hz, J₂ = 6.1 Hz), 2.45-2.65 (2H, m), 1.8-2.25 (4H, m)。 Example 5
(5R ^* , 6S ^* )-6- (4-Bromophenyl) -3- (3,5-dichlorophenyl) -2-thioxo-1,3-diazaspiro [4.4] nonan-4-one

6- (4-Bromophenyl) -3- (3,5-dichlorophenyl) -4-oxo-2-thioxo-1,3-diazaspiro [4.4] nonane-1-carboxylic acid tert-butyl ester (42 mg, 74 μmol) (Production Example 10) was added to a TFA / DCM / H ₂ O (1/1 / 0.1) solution (1 mL) at RT. After 30 minutes, the reaction mixture was concentrated to give a beige solid which was washed with pentane to give 6- (4-bromophenyl) -3- (3,5-dichlorophenyl) -2-thioxo- 1,3-diazaspiro [4.4] nonan-4-one (21 mg, beige solid) was obtained. ¹ H NMR (CDCl ₃ ): 8.39 (1H, s), 7.51 (2H, d, J = 8.4 Hz), 7.35 (1H, m), 7.19 (2H, d, J = 8.4 Hz), 6.44 (2H, m), 3.36 (1H, dd, J ₁ = 12.9 Hz, J ₂ = 6.1 Hz), 2.45-2.65 (2H, m), 1.8-2.25 (4H, m).

実施例５と同じ方法を用いて、(５Ｒ^＊,６Ｓ^＊)−６−(４−ブロモフェニル)−３−(３,５−ジクロロフェニル)−２,４−ジオキソ−１,３−ジアザスピロ[４.４]ノナン−１−カルボン酸ｔｅｒｔ−ブチルエステル（８０ｍｇ、０．１４ｍｍｏｌ）（実施例４）を、(５Ｒ^＊,６Ｓ^＊)−６−(４−ブロモフェニル)−３−(３,５−ジクロロフェニル)−１,３−ジアザスピロ[４.４]ノナン−２,４−ジオン（５８ｍｇ）に変換した。¹H NMR (CDCl₃)：7.48 (2H, d, J = 8.3 Hz), 7.32 (1H, m), 7.18 (2H, d, J = 8.3 Hz ), 6.68 (2H, m), 6.54 (1H, br s), 3.22 (1H, dd, J₁ = 12.7 Hz, J₂ = 6.2 Hz), 2.45-2.65 (2H, m), 1.9-2.25 (4H, m)。 Example 6
(5R ^* , 6S ^* )-6- (4-Bromophenyl) -3- (3,5-dichlorophenyl) -1,3-diazaspiro [4.4] nonane-2,4-dione

Using the same method as in Example 5, (5R ^* , 6S ^* )-6- (4-bromophenyl) -3- (3,5-dichlorophenyl) -2,4-dioxo-1,3-diazaspiro [4 .4] Nonane-1-carboxylic acid tert-butyl ester (80 mg, 0.14 mmol) (Example 4) was converted to (5R ^* , 6S ^* )-6- (4-bromophenyl) -3- (3,5 -Dichlorophenyl) -1,3-diazaspiro [4.4] nonane-2,4-dione (58 mg). ¹ H NMR (CDCl ₃ ): 7.48 (2H, d, J = 8.3 Hz), 7.32 (1H, m), 7.18 (2H, d, J = 8.3 Hz), 6.68 (2H, m), 6.54 (1H, br s), 3.22 (1H, dd, J ₁ = 12.7 Hz, J ₂ = 6.2 Hz), 2.45-2.65 (2H, m), 1.9-2.25 (4H, m).

６−(４−ブロモフェニル)−３−(３,５−ジクロロフェニル)−１−メチル−１,３−ジアザスピロ[４.４]ノナン−２,４−ジオン（１ｇ、２．１ｍｍｏｌ）（実施例１）およびＣｕＣＮ（０．４５ｇ、５ｍｍｏｌ）の混合物を、ＮＭＰ中で１８０℃まで６時間加熱した。冷却後に、該反応混合物を、氷およびエチレンジアミンの混合物に注ぎ、そしてこのものをＤＣＭを用いて２回抽出した。該褐色残渣をシリカゲルクロマトグラフィー精製を行なって、ベージュ色固体の４−[(５Ｒ^＊,６Ｓ^＊)−３−(３,５−ジクロロフェニル)−１−メチル−２,４−ジオキソ−１,３−ジアザスピロ[４.４]ノナ−６−イル]ベンゾニトリルを得た。¹H NMR (CDCl₃)：7.62 (2H, d, J = 8.1 Hz), 7.25-7.3 (3H, m), 6.67 (2H, br s), 3.45 (1H, dd, J₁ = 12.8 Hz, J₂ = 6.4 Hz), 3.16 (3H, s), 2.4-2.7 (1H, m), 1.8-2.4 (5H, m)。 Example 7
4-[(5R ^* , 6S ^* )-3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3-diazaspiro [4.4] nonan-6-yl] benzonitrile

6- (4-Bromophenyl) -3- (3,5-dichlorophenyl) -1-methyl-1,3-diazaspiro [4.4] nonane-2,4-dione (1 g, 2.1 mmol) (Example) A mixture of 1) and CuCN (0.45 g, 5 mmol) was heated to 180 ° C. in NMP for 6 hours. After cooling, the reaction mixture was poured into a mixture of ice and ethylenediamine and this was extracted twice with DCM. The brown residue was purified by silica gel chromatography to give 4-[(5R ^* , 6S ^* )-3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3 as a beige solid. -Diazaspiro [4.4] non-6-yl] benzonitrile was obtained. ¹ H NMR (CDCl ₃ ): 7.62 (2H, d, J = 8.1 Hz), 7.25-7.3 (3H, m), 6.67 (2H, br s), 3.45 (1H, dd, J ₁ = 12.8 Hz, J ₂ = 6.4 Hz), 3.16 (3H, s), 2.4-2.7 (1H, m), 1.8-2.4 (5H, m).

(５Ｒ^＊,６Ｓ^＊)−６−(４−ブロモフェニル)−３−(３,５−ジクロロフェニル)−１−メチル−１,３−ジアザスピロ[４.４]ノナン−２,４−ジオン（８０ｍｇ、０．１７ｍｍｏｌ）（実施例１）、フェニルボロン酸（７３ｍｇ、０．６ｍｍｏｌ）、(Ｐｈ_３Ｐ)_４Ｐｄ（２０ｍｇ、０．０２ｍｍｏｌ）およびＫ_２ＣＯ_３（８０ｍｇ、０．６ｍｍｏｌ）のＤＭＥ（１．５ｍＬ）および水（５０μＬ）混合液の溶液を、８０℃で１２時間加熱した。該不溶性物質をろ過して除き、そして該ろ液を濃縮した。クロマトグラフィー精製後に、白色固体の(５Ｒ^＊,６Ｓ^＊)−６−ビフェニル−４−イル−３−(３,５−ジクロロフェニル)−１−メチル−１,３−ジアザスピロ[４.４]ノナン−２,４−ジオン（２０ｍｇ）を得た。¹H NMR (CDCl₃)：7.5-7.6 (4H, m), 7.3-7.5 (3H, m), 7.15-7.3 (3H, m), 6.64 (2H, m), 3.45 (1H, dd, J₁ = 12.4 Hz, J₂ = 6.1 Hz), 3.18 (3H, s), 2.5-2.75 (1H, m), 1.8-2.45 (5H, m)。 Example 8
(5R ^* , 6S ^* )-6-biphenyl-4-yl-3- (3,5-dichlorophenyl) -1-methyl-1,3-diazaspiro [4.4] nonane-2,4-dione

(5R ^* , 6S ^* )-6- (4-Bromophenyl) -3- (3,5-dichlorophenyl) -1-methyl-1,3-diazaspiro [4.4] nonane-2,4-dione (80 mg 0.17 mmol) (Example 1), phenylboronic acid (73 mg, 0.6 mmol), (Ph ₃ P) ₄ Pd (20 mg, 0.02 mmol) and K ₂ CO ₃ (80 mg, 0.6 mmol) in DME A solution of (1.5 mL) and water (50 μL) mixture was heated at 80 ° C. for 12 hours. The insoluble material was filtered off and the filtrate was concentrated. After chromatographic purification, (5R ^* , 6S ^* )-6-biphenyl-4-yl-3- (3,5-dichlorophenyl) -1-methyl-1,3-diazaspiro [4.4] nonane- 2,4-dione (20 mg) was obtained. ¹ H NMR (CDCl ₃ ): 7.5-7.6 (4H, m), 7.3-7.5 (3H, m), 7.15-7.3 (3H, m), 6.64 (2H, m), 3.45 (1H, dd, J ₁ = 12.4 Hz, J ₂ = 6.1 Hz), 3.18 (3H, s), 2.5-2.75 (1H, m), 1.8-2.45 (5H, m).

実施例８に記載する方法を用いて、(５Ｒ^＊,６Ｓ^＊)−６−(４−ブロモフェニル)−３−(３,５−ジクロロフェニル)−１−メチル−１,３−ジアザスピロ[４.４]ノナン−２,４−ジオン（８０ｍｇ、０．１７ｍｍｏｌ）（実施例１）を、４−フルオロフェニルボロン酸（７１．４ｍｇ、０．５１ｍｍｏｌ）と反応させて、白色固体の上記標題化合物（１２ｍｇ）を得た。¹H NMR (CDCl₃)：7.45-7.55 (4H, m), 7.05-7.25 (5H, m), 6.62 (2H, m), 3.46 (1H, dd, J₁ = 12.9 Hz, J₂ = 6.3 Hz), 3.18 (3H, s), 2.5-2.75 (1H, m), 1.85-2.45 (5H, m)。 Example 9
^{(5R *, 6S *) -3-} (3,5- dichlorophenyl) -6- (4 ^'- fluoro-biphenyl-4-yl) -1-methyl-1,3-diazaspiro [4.4] nonane -2, 4-dione

Using the method described in Example 8, (5R ^* , 6S ^* )-6- (4-bromophenyl) -3- (3,5-dichlorophenyl) -1-methyl-1,3-diazaspiro [4. 4] Nonane-2,4-dione (80 mg, 0.17 mmol) (Example 1) was reacted with 4-fluorophenylboronic acid (71.4 mg, 0.51 mmol) to give the title compound as a white solid ( 12 mg) was obtained. ¹ H NMR (CDCl ₃ ): 7.45-7.55 (4H, m), 7.05-7.25 (5H, m), 6.62 (2H, m), 3.46 (1H, dd, J ₁ = 12.9 Hz, J ₂ = 6.3 Hz ), 3.18 (3H, s), 2.5-2.75 (1H, m), 1.85-2.45 (5H, m).

(５Ｒ^＊,６Ｓ^＊)−６−(４−ブロモフェニル)−３−(３,５−ジクロロフェニル)−１−メチル−１,３−ジアザスピロ[４,５]デカン−２,４−ジオン（１ｇ、２．３ｍｍｏｌ）（実施例３）およびＣｕＣＮ（０．３８ｇ、４．２ｍｍｏｌ）から出発して、実施例７と同じ方法を用いて、白色固体の上記標題化合物（０．８ｇ、ｍｐ＝１９２℃）を得た。¹H NMR (CDCl₃)：7.59 (2H, d, J = 8.3 Hz), 7.25-7.35 (3H, m), 6.89 (2H, m), 3.04 (3H, s), 3.02 (1H, dd, J₁ = 12.9 Hz, J₂ = 3.5 Hz), 2.6 (1H, dq), 2.1-2.3 (1H, m), 1.8-2.05 (5H, m), 1.3-1.6 (1H, m)。 Example 10
4-[(5R ^* , 6S ^* )-3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3-diazaspiro [4.5] dec-6-yl] -benzonitrile

(5R ^* , 6S ^* )-6- (4-Bromophenyl) -3- (3,5-dichlorophenyl) -1-methyl-1,3-diazaspiro [4,5] decane-2,4-dione (1 g 2.3 mmol) (Example 3) and CuCN (0.38 g, 4.2 mmol) using the same method as Example 7 using the same method as the title compound (0.8 g, mp = 192) as a white solid. C). ¹ H NMR (CDCl ₃ ): 7.59 (2H, d, J = 8.3 Hz), 7.25-7.35 (3H, m), 6.89 (2H, m), 3.04 (3H, s), 3.02 (1H, dd, J ₁ = 12.9 Hz, J ₂ = 3.5 Hz), 2.6 (1H, dq), 2.1-2.3 (1H, m), 1.8-2.05 (5H, m), 1.3-1.6 (1H, m).

ＴＦＡ（７２μＬ、０．９ｍｍｏｌ）を、ＤＣＭ（２００ｍＬ）中、製造例１５（４．１５ｇ、１０．４ｍｍｏｌ）およびＮ−(メトキシメチル)−Ｎ−(トリメチルシリルメチル)ベンジルアミン（２．９ｇ、１１．９ｍｍｏｌ）の冷（５℃）溶液に加えた。ＲＴで２０時間後に、該溶液を希水酸化アンモニウムおよび水で洗浄した。該有機層をＮａ_２ＳＯ_４で乾燥し、そして濃縮して固体（７．５ｇ）を得て、このものをシリカゲルクロマトグラフィー精製（溶出液はＤＣＭ／アセトンの９５／５である）を行なって、白色固体の上記標題化合物（３．３ｇ）（ｍｐ＝２２４℃）を得た。¹H NMR (CDCl₃)：7.65 (2H, d, J = 8.3 Hz), 7.45 (2H, d, J = 6.9 Hz), 7.25-7.40 (6H, m), 6.53 (2H, d, J = 1.5 Hz), 4.62 (1H, dd, J₁ = 10.3 Hz, J₂ = 7 Hz), 4.04 (1H, d, J = 13.1 Hz), 3.79 (1H, d, J = 1 Hz), 3.70 (1H, d, J = 10.2 Hz), 3.40-3.50 (2H, m), 3.02 (1H, d, J = 10.2 Hz), 2.71 (3H, s)。 Example 11
4-[(5S ^* , 9R ^* )-1-acetyl-7-benzyl-3- (3,5-dichlorophenyl) -2,4-dioxo-1,3,7-triazaspiro [4.4] nona-9 -Yl] -benzonitrile

TFA (72 μL, 0.9 mmol) was prepared in DCM (200 mL) with Preparation 15 (4.15 g, 10.4 mmol) and N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine (2.9 g, 11 .9 mmol) in a cold (5 ° C.) solution. After 20 hours at RT, the solution was washed with dilute ammonium hydroxide and water. The organic layer was dried over Na ₂ SO ₄ and concentrated to give a solid (7.5 g) which was purified by silica gel chromatography (eluent is 95/5 DCM / acetone). The title compound (3.3 g) (mp = 224 ° C.) was obtained as a white solid. ¹ H NMR (CDCl ₃ ): 7.65 (2H, d, J = 8.3 Hz), 7.45 (2H, d, J = 6.9 Hz), 7.25-7.40 (6H, m), 6.53 (2H, d, J = 1.5 Hz), 4.62 (1H, dd, J ₁ = 10.3 Hz, J ₂ = 7 Hz), 4.04 (1H, d, J = 13.1 Hz), 3.79 (1H, d, J = 1 Hz), 3.70 (1H, d, J = 10.2 Hz), 3.40-3.50 (2H, m), 3.02 (1H, d, J = 10.2 Hz), 2.71 (3H, s).

実施例１１（８．９ｇ、１６．７ｍｍｏｌ）、ＴＥＡ（３．８ｍＬ）およびピロリジン（２．２ｍＬ）のＴＨＦ（２７０ｍＬ）混合物を、２時間３０分間還流した。該混合物を真空下で濃縮し、そしてＤＣＭ中に溶かし、次いで水洗した。該有機層をＭｇＳＯ_４で乾燥し、そして濃縮した。得られた固体をシリカゲルクロマトグラフィー精製（溶出液はＤＣＭ／ＭｅＯＨの９５／５である）を行なって、白色固体の上記標題化合物（９．３ｇ）（ｍｐ＝２００℃）を得た。¹H NMR (DMSO-d₆)：9.32 (1H, br s), 7.84 (2H, d, J = 8.2 Hz), 7.60 (1H, m), 7.25-7.45 (7H, m), 6.74 (2H, d, J = 1.9 Hz), 3.65-3.9 (3H, m), 3-3.3 (4H, m)。 Example 12
4-[(5S ^* , 9R ^* )-7-benzyl-3- (3,5-dichlorophenyl) -2,4-dioxo-1,3,7-triazaspiro [4.4] non-9-yl] benzo Nitrile

A mixture of Example 11 (8.9 g, 16.7 mmol), TEA (3.8 mL) and pyrrolidine (2.2 mL) in THF (270 mL) was refluxed for 2 hours 30 minutes. The mixture was concentrated in vacuo and taken up in DCM then washed with water. The organic layer was dried over MgSO ₄ and concentrated. The obtained solid was purified by silica gel chromatography (eluent is 95/5 of DCM / MeOH) to give the title compound (9.3 g) (mp = 200 ° C.) as a white solid. ¹ H NMR (DMSO-d ₆ ): 9.32 (1H, br s), 7.84 (2H, d, J = 8.2 Hz), 7.60 (1H, m), 7.25-7.45 (7H, m), 6.74 (2H, d, J = 1.9 Hz), 3.65-3.9 (3H, m), 3-3.3 (4H, m).

実施例１１および１２と同じ方法を用いるが、製造例１５の代わりに製造例１６を用いて、白色固体の上記標題化合物を得た。¹H NMR (DMSO-d₆)：10.3 (1H, br s), 7.79 (2H, d), 7.62 (3H, m), 7.35-7.55 (3H, m), 7.20 (2H, d, J = 8.4 Hz), 6.73 (2H, d, J = 1.9 Hz), 4.6-4.9 (3H, m), 4.2-4.4 (2H, m), 3.65-3.8 (1H, m), 3.25-3.5 (1H, m)。 Example 13
(5S ^* , 9R ^* )-7-benzyl-9- (4-bromophenyl) -3- (3,5-dichlorophenyl) -1,3,7-triazaspiro [4.4] nonane-2,4-dione

Using the same method as Examples 11 and 12, but using Preparation 16 instead of Preparation 15, the title compound was obtained as a white solid. ¹ H NMR (DMSO-d ₆ ): 10.3 (1H, br s), 7.79 (2H, d), 7.62 (3H, m), 7.35-7.55 (3H, m), 7.20 (2H, d, J = 8.4 Hz), 6.73 (2H, d, J = 1.9 Hz), 4.6-4.9 (3H, m), 4.2-4.4 (2H, m), 3.65-3.8 (1H, m), 3.25-3.5 (1H, m) .

実施例１２（６．２５ｇ、１２．７ｍｍｏｌ）を、ＮａＨ（油中６０％、０．７５ｇ、１８．８ｍｍｏｌ）の乾燥ＤＭＦ（６０ｍＬ）懸濁液に加えた。ＲＴで２時間後に、ヨウ化メチル（１．２ｍＬ、１９．２ｍｍｏｌ）を加えた。４８時間後に、該混合物を真空下で濃縮し、そしてＤＣＭおよび水に溶かした。該有機層をＭｇＳＯ_４で乾燥し、そして乾固するまで濃縮した。該残渣をシリカゲルクロマトグラフィー精製（ＤＣＭ／アセトンの９５／５を使用）を行なって、白色固体の上記標題化合物（５．１ｇ）（ｍｐ＝１６４℃）を得た。¹H NMR (CDCl₃)：7.61 (2H, d, J = 8.1 Hz), 7.25-7.4 (8H, m), 6.65 (2H, d, J = 1.6 Hz), 3.7-3.9 (3H, m), 3.1-3.35 (2H, m), 3.22 (3H, s), 2.98 (2H, d, J = 10.9 Hz)。 Example 14
4-[(5S ^* , 9R ^* )-7-benzyl-3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] nona-9 -Yl] benzonitrile

Example 12 (6.25 g, 12.7 mmol) was added to a dry DMF (60 mL) suspension of NaH (60% in oil, 0.75 g, 18.8 mmol). After 2 hours at RT, methyl iodide (1.2 mL, 19.2 mmol) was added. After 48 hours, the mixture was concentrated in vacuo and dissolved in DCM and water. The organic layer was dried over MgSO ₄ and concentrated to dryness. The residue was purified by silica gel chromatography (using 95/5 of DCM / acetone) to give the title compound (5.1 g) (mp = 164 ° C.) as a white solid. ¹ H NMR (CDCl ₃ ): 7.61 (2H, d, J = 8.1 Hz), 7.25-7.4 (8H, m), 6.65 (2H, d, J = 1.6 Hz), 3.7-3.9 (3H, m), 3.1-3.35 (2H, m), 3.22 (3H, s), 2.98 (2H, d, J = 10.9 Hz).

クロロギ酸１−クロロエチル（４．４ｍＬ、４０．３ｍｍｏｌ）を、ＤＣＭ（２５０ｍＬ）中、実施例１４（５．１ｇ、１０．１ｍｍｏｌ）の冷（５℃）溶液に加えた。５℃で１時間後に、該反応混合物をＲＴで２０時間撹拌した。該溶液を乾固するまで濃縮し、次いでＭｅＯＨ（３５０ｍＬ）中で３時間還流させた。真空下で濃縮後に、該油状残渣をＥｔ_２Ｏ中でトリチュレートして、目的化合物の塩酸塩（４．９ｇ）を得た。塩基性とした後に、該生成物をシリカゲルクロマトグラフィー精製（ＤＣＭ／ＭｅＯＨの９０／１０を使用）を行なって、アモルファス固体の上記標題化合物（３．３５ｇ）を得た。¹H NMR (CDCl₃)：7.64 (2H, d, J =8.4 Hz), 7.25-7.32 (3H, m), 6.72 (2H, d, J = 2 Hz), 3.6-3.75 (2H, m), 3.35-3.55 (3H, m), 3.20 (3H, s), 2.16 (1H, br s)。 Example 15
4-[(5S ^* , 9R ^* )-3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] non-9-yl] benzo Nitrile

1-Chloroethyl chloroformate (4.4 mL, 40.3 mmol) was added to a cold (5 ° C.) solution of Example 14 (5.1 g, 10.1 mmol) in DCM (250 mL). After 1 hour at 5 ° C., the reaction mixture was stirred at RT for 20 hours. The solution was concentrated to dryness and then refluxed in MeOH (350 mL) for 3 hours. After concentration in vacuo, the oily residue was triturated in Et ₂ O to give the desired compound hydrochloride (4.9 g). After basification, the product was purified by silica gel chromatography (using DCM / MeOH 90/10) to give the title compound (3.35 g) as an amorphous solid. ¹ H NMR (CDCl ₃ ): 7.64 (2H, d, J = 8.4 Hz), 7.25-7.32 (3H, m), 6.72 (2H, d, J = 2 Hz), 3.6-3.75 (2H, m), 3.35-3.55 (3H, m), 3.20 (3H, s), 2.16 (1H, br s).

Examples 15A and 15B
Compound 15 was resolved into its enantiomers Examples 15A and 15B below using HPLC (Chiralpak-AD column, solvent system using hexane: MeOH: EtOH or carbon dioxide). There are a number of alternative ways to resolve the compounds of the present invention into their enantiomers.

Chiralpak-ADカラム（溶出液として、二酸化炭素：ＭｅＯＨを使用する）を用いる保持時間は、５．７４分である。[α]_Ｄ＝＋９５．２（ｃ＝１、ＭｅＯＨ）。 Example 15a
4-[(5S, 9R) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] non-9-yl] benzonitrile

The retention time using a Chiralpak-AD column (using carbon dioxide: MeOH as the eluent) is 5.74 minutes. [[alpha]] _D = +95.2 (c = 1, MeOH).

Chiralpak-ADカラム（溶出液として、二酸化炭素：ＭｅＯＨを使用する）を用いる保持時間は、１３．３１分である。[α]_Ｄ＝−９６．５（ｃ＝１、ＭｅＯＨ）。 Example 15b
4-[(5R, 9S) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] non-9-yl] benzonitrile

The retention time using a Chiralpak-AD column (using carbon dioxide: MeOH as the eluent) is 13.31 minutes. [[alpha]] _D = -96.5 (c = 1, MeOH).

実施例１５（１２．４ｍｇ、０．０３ｍｍｏｌ）のＴＨＦ（１ｍＬ）溶液を、酸クロリドまたはスルホニルクロリド（０．０４５ｍｍｏｌ）に加えた。担体塩基ＰＳ−ＤＩＥＡ（Argonaut、３．５６ｍｍｏｌ／ｇ、１５ｍｇ、０．０５ｍｍｏｌ）の添加後に、該懸濁液をＲＴで終夜撹拌した。次いで、スカベンジャーＰＳ−トリサミン（Argonaut、３．６５ｍｍｏｌ／ｇ、３６ｍｇ、０．１３ｍｍｏｌ）を加え、そして該混合物を終夜の撹拌後にろ過した。必要時に、該得られた溶液をＰＳ−イソシアネート（Argonaut、１．４４ｍｍｏｌ／ｇ、９０ｍｇ、０．１３ｍｍｏｌ）を用いて終夜処理した。ろ過および乾固するまで蒸発後に、上記の式（Ｉａｃ）（式中、Ｒ_９は表１に示す基を有する）を有する化合物を得た。各化合物について、純度およびＬＣマスの結果を報告する（ＬＣＭＳ条件：LC Micromass platform（APCI+, DAD (210-400 nm))、カラム：TSK gel Super ODS ４．６ｍｍ ID × ５ｃｍ、流速：２．７５ｍＬ／分、勾配：１００％溶出液Ａ〜１００％溶出液Ｂを２分間および１００％溶出液Ｂのプラトーを１分間）。溶出液ＡはＨ_２Ｏ（０．０５％ＴＦＡ）であり、溶出液ＢはＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡ（８０／２０／０．０５）である。以下の本明細書の表中、「Ex」は「実施例番号」と、「structure」は「構造式」と、「method」は「方法」と、「Quantity」は「量」と、「Retention time」は「保持時間」と、および「Analysis」は「分析」と訳す。

Examples 16-21

A solution of Example 15 (12.4 mg, 0.03 mmol) in THF (1 mL) was added to acid chloride or sulfonyl chloride (0.045 mmol). After the addition of the carrier base PS-DIEA (Argonaut, 3.56 mmol / g, 15 mg, 0.05 mmol), the suspension was stirred at RT overnight. Scavenger PS-Trisamine (Argonaut, 3.65 mmol / g, 36 mg, 0.13 mmol) was then added and the mixture was filtered after overnight stirring. When necessary, the resulting solution was treated with PS-isocyanate (Argonaut, 1.44 mmol / g, 90 mg, 0.13 mmol) overnight. After filtration and evaporation to dryness, a compound having the above formula (Iac) (wherein R ₉ has the groups shown in Table 1) was obtained. The purity and LC mass results are reported for each compound (LCMS conditions: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 2.75 mL. / Min, gradient: 100% eluent A to 100% eluent B for 2 minutes and 100% eluent B plateau for 1 minute). The eluent A is H ₂ O (0.05% TFA), and the eluent B is CH ₃ CN / H ₂ O / TFA (80/20 / 0.05). In the tables of this specification, “Ex” is “Example Number”, “structure” is “Structural Formula”, “method” is “Method”, “Quantity” is “Quantity”, “Retention” “time” is translated as “holding time”, and “Analysis” is translated as “analysis”.

実施例１５（１８．７ｇ、０．０４５ｍｍｏｌ）のＴＨＦ（１ｍＬ）溶液を、スルホニルクロリド（０．０３ｍｍｏｌ）に加えた。担体塩基ＰＳ−ＤＩＥＡ（Argonaut、３．５６ｍｍｏｌ／ｇ、１５ｍｇ、０．０５ｍｍｏｌ）の添加後に、該懸濁液をＲＴで終夜撹拌した。次いで、スカベンジャーＰＳ−イソシアネート（Argonaut、１．４４ｍｏｌ／ｇ、９０ｍｇ、０．１３ｍｍｏｌ）を加え、そして該混合物をＲＴで終夜撹拌した。ろ過および乾固するまで蒸発後に、式（Ｉａｄ）（式中、Ｒ_１８ａおよび_１８ｂは表２に示す基を有する）を有する目的化合物を得た。各化合物について、純度およびＬＣマスの結果を報告する（ＬＣＭＳ条件：LC Micromass platform (APCI＋, DAD (210-400nm))、カラム：TSK gel Super ODS 4.6 mm ID × 5 cm、流速：2.75 mL／分、勾配：１００％溶出液Ａ〜１００％溶出液Ｂを２分間および１００％溶出液Ｂのプラトーを１分間）。溶出液ＡはＨ_２Ｏ（０．０５％ＴＦＡ）であり、溶出液ＢはＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡ（８０／２０／０．０５）である。

Examples 22-24

A solution of Example 15 (18.7 g, 0.045 mmol) in THF (1 mL) was added to the sulfonyl chloride (0.03 mmol). After the addition of the carrier base PS-DIEA (Argonaut, 3.56 mmol / g, 15 mg, 0.05 mmol), the suspension was stirred at RT overnight. Scavenger PS-isocyanate (Argonaut, 1.44 mol / g, 90 mg, 0.13 mmol) was then added and the mixture was stirred at RT overnight. After filtration and evaporation to dryness, the target compound having the formula (Iad) (wherein R _18a and _18b have the groups shown in Table 2) was obtained. For each compound, the purity and LC mass results are reported (LCMS conditions: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 2.75 mL / min. Gradient: 100% eluent A to 100% eluent B for 2 minutes and 100% eluent B plateau for 1 minute). The eluent A is H ₂ O (0.05% TFA), and the eluent B is CH ₃ CN / H ₂ O / TFA (80/20 / 0.05).

４−[(５Ｓ,９Ｒ)−３−(３,５−ジクロロフェニル)−１−メチル−２,４−ジオキソ−１,３,７−トリアザスピロ[４.４]ノナン−９−イル]ベンゾニトリル（実施例１５ａ）（０．１１ｇ、０．２６ｍｍｏｌ）および３−(クロロスルホニル)安息香酸（０．０５８ｇ、０．２６ｍｍｏｌ）のアセトンおよび水（１：１ｍＬ）の混合物に、室温で炭酸水素ナトリウムを加えた。該反応混合物を室温で４０分間撹拌し、１Ｎ塩酸（１ｍＬ）をゆっくりと加えることによってクエンチし、ＤＣＭ（２×２０ｍＬ）およびブライン（２５ｍ）の間で分配した。該ＤＣＭ層を硫酸ナトリウムで乾燥し、濃縮し、シリカゲルクロマトグラフィー（ＤＣＭおよびＭｅＯＨを使用）を用いてカラム精製して、標題化合物（０．１２ｇ）を得た。保持時間：３．３９分。YMC S5 Combiscreen ODS 4.6 × 50 mm (４分間勾配)。溶媒Ａは、１０％ＭｅＯＨ、９０％水および０．２％リン酸である。溶媒Ｂは、９０％ＭｅＯＨ、１０％水および０．２％リン酸である。 Example 24a
3-[(5S, 9R) -9- (4-Cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] Nonane-7-sulfonyl] -benzoic acid

4-[(5S, 9R) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] nonan-9-yl] benzonitrile ( Example 15a) To a mixture of 0.11 g, 0.26 mmol) and 3- (chlorosulfonyl) benzoic acid (0.058 g, 0.26 mmol) in acetone and water (1: 1 mL) was added sodium bicarbonate at room temperature. added. The reaction mixture was stirred at room temperature for 40 minutes, quenched by the slow addition of 1N hydrochloric acid (1 mL) and partitioned between DCM (2 × 20 mL) and brine (25 m). The DCM layer was dried over sodium sulfate, concentrated and column purified using silica gel chromatography (using DCM and MeOH) to give the title compound (0.12 g). Retention time: 3.39 minutes. YMC S5 Combiscreen ODS 4.6 x 50 mm (4-minute gradient). Solvent A is 10% MeOH, 90% water and 0.2% phosphoric acid. Solvent B is 90% MeOH, 10% water and 0.2% phosphoric acid.

実施例２４ｂは、４−[(５Ｒ,９Ｓ)−３−(３,５−ジクロロフェニル)−１−メチル−２,４−ジオキソ−１,３,７−トリアザスピロ[４.４]ノナ−９−イル]ベンゾニトリル（０．４０４ｇ、０．９７ｍｍｏｌ）（実施例１５ｂ）から出発して、実施例２４ａに記載するのと同様な方法で製造して、標題化合物（０．３３１ｇ）を得た。保持時間は３．３６分である。YMC S5 ODS 4.6 × 50 mm（４分間の勾配）。溶媒Ａは、１０％ＭｅＯＨ、９０％水および０．２％リン酸である。溶媒Ｂは、９０％ＭｅＯＨ、１０％水および０．２％リン酸である。 Example 24b
3-[(5R, 9S) -9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] Nonane-7-sulfonyl] -benzoic acid

Example 24b represents 4-[(5R, 9S) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] non-9- Il] benzonitrile (0.404 g, 0.97 mmol) (Example 15b) was prepared in a similar manner as described in Example 24a to give the title compound (0.331 g). The retention time is 3.36 minutes. YMC S5 ODS 4.6 x 50 mm (4-minute gradient). Solvent A is 10% MeOH, 90% water and 0.2% phosphoric acid. Solvent B is 90% MeOH, 10% water and 0.2% phosphoric acid.

ＰＳ−カルボジイミド（Argonaut、０．９６ｍｍｏｌ／ｇ、７４ｍｇ、０．０７１ｍｍｏｌ）のヒドロキシアザベンゾトリアゾール溶液（１５０ｍＭ ＤＣＭ｛２５％ＤＭＦ｝、０．０５ｍｍｏｌ）（０．３３ｍＬ）の懸濁液に、酸溶液（６６ｍＭ ＤＣＭ｛２０％ＤＭＦ｝、０．０３３ｍｍｏｌ）（０．５ｍＬ）および実施例１５（１２０ｍＭ ＤＣＭ｛２０％ＤＣＭ｝、０．０３ｍｍｏｌ）溶液（０．２５ｍＬ）を加えた。ＲＴで２４時間後に、該混合物をＰＳ−トリサミン（Argonaut、３．６５ｍｍｏｌ／ｇ、６５ｍｇ、０．２４ｍｍｏｌ）を用いて終夜処理した。該ろ過した溶液を乾固するまで蒸発させた後に、式（Ｉａｅ）（式中、Ｒ_１６は表３に示す基を有する）を有する化合物を、ＳＣＸカートリッジ精製によって得た。Ｎ−Ｂｏｃおよび／またはＣＯ_２ｔＢｕ保護の酸の場合には、該化合物をＤＣＭ／ＴＦＡ（１：１）溶液を用いてＲＴで２時間、最初に処理した。

Examples 25-36

A suspension of PS-carbodiimide (Argonaut, 0.96 mmol / g, 74 mg, 0.071 mmol) in a hydroxyazabenzotriazole solution (150 mM DCM {25% DMF}, 0.05 mmol) (0.33 mL) in an acid solution (66 mM DCM {20% DMF}, 0.033 mmol) (0.5 mL) and Example 15 (120 mM DCM {20% DCM}, 0.03 mmol) solution (0.25 mL) were added. After 24 hours at RT, the mixture was treated with PS-trisamine (Argonaut, 3.65 mmol / g, 65 mg, 0.24 mmol) overnight. After evaporation of the filtered solution to dryness, a compound having the formula (Iae), where R ₁₆ has the groups shown in Table 3, was obtained by SCX cartridge purification. In the case of N-Boc and / or CO ₂ tBu protected acid, the compound was first treated with DCM / TFA (1: 1) solution at RT for 2 h.

５−ホルミル−３−チオフェンカルボン酸（４５ｍｇ、０．２９ｍｍｏｌ）を、硫酸ナトリウム（１００ｍｇ）および実施例１５（１００ｍｇ、０．２４ｍｍｏｌ）の１,２−ＤＣＥ（４ｍＬ）の懸濁液に加えた。室温で２０時間後に、トリアセトキシ水素化ホウ素ナトリウム（７５ｍｇ、０．３４ｍｍｏｌ）を加え、そして該反応混合物を室温で２４時間撹拌した。次いで、水を加え、そして該反応混合物を、そのものにＳＯ_２をバブルするころによって酸性とした。該有機層を分離し、そして該水相をＤＣＭで２回抽出した。該有機相を合わせて水洗し、硫酸ナトリウムで乾燥し、そして濃縮した。該得られた固体をＭｅＯＨ中で結晶化して、白色結晶の目的化合物（１２０ｍｇ）（ｍｐ＝１８８℃）を得た。 Example 37
5-[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4. 4] Nona-7-ylmethyl] thiophene-3-carboxylic acid

5-Formyl-3-thiophenecarboxylic acid (45 mg, 0.29 mmol) was added to a suspension of sodium sulfate (100 mg) and Example 15 (100 mg, 0.24 mmol) in 1,2-DCE (4 mL). . After 20 hours at room temperature, sodium triacetoxyborohydride (75 mg, 0.34 mmol) was added and the reaction mixture was stirred at room temperature for 24 hours. Then, water was added, and the reaction mixture was acidified by roller to bubble the SO ₂ to itself. The organic layer was separated and the aqueous phase was extracted twice with DCM. The organic phases were combined, washed with water, dried over sodium sulfate and concentrated. The obtained solid was crystallized in MeOH to obtain the target compound (120 mg) (mp = 188 ° C.) as white crystals.

４−[(５Ｓ,９Ｒ)−３−(３,５−ジクロロフェニル)−１−メチル−２,４−ジオキソ−１,３,７−トリアザスピロ[４.４]ノナ−９−イル]ベンゾニトリル（０．１ｇ、０．２４ｍｍｏｌ）（実施例１５ａ）の１,２−ＤＣＥ（４ｍＬ）溶液に、５−ホルミル−３−チオフェンカルボン酸（０．０４５ｇ、０．２９ｍｍｏｌ）および硫酸ナトリウム（１５０ｍｇ）を窒素下、室温で連続して加えた。該内容物を室温で２０時間撹拌し、そしてトリアセトキシ水素化ホウ素ナトリウム（０．０７５ｇ、０．３３６ｍｍｏｌ）を加えた。該反応を室温で６時間続けて、そして水（１５ｍＬ）を加えることによってクエンチした。ＤＣＭ（１５ｍＬ）を加え、そして二酸化硫黄ガスを該反応混合物に１０分間かけてバブルし、そして該内容物を分液ろうとに移した。該有機層を分離し、ブライン（２×２０ｍ）で洗浄し、硫酸ナトリウムで乾燥し、減圧下で濃縮し、そしてシリカゲルカラムクロマトグラフィー（ＤＣＭおよびＭｅＯＨを使用）によって精製して、標題化合物（０．１ｇ）を得た。保持時間は、３．０９分である。YMC S5 Combiscreen 4.6 × 50 mm（４分間の勾配）。溶媒Ａは、１０％ＭｅＯＨ、９０％水および０．２％リン酸である。溶媒Ｂは、９０％ＭｅＯＨ、１０％水および０．２％リン酸である。 Example 37a
5-[(5S, 9R) -9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] Non-7-ylmethyl] thiophene-3-carboxylic acid

4-[(5S, 9R) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] non-9-yl] benzonitrile ( To a solution of 0.1 g, 0.24 mmol) (Example 15a) in 1,2-DCE (4 mL) was added 5-formyl-3-thiophenecarboxylic acid (0.045 g, 0.29 mmol) and sodium sulfate (150 mg). Added continuously at room temperature under nitrogen. The contents were stirred at room temperature for 20 hours and sodium triacetoxyborohydride (0.075 g, 0.336 mmol) was added. The reaction was continued at room temperature for 6 hours and quenched by adding water (15 mL). DCM (15 mL) was added and sulfur dioxide gas was bubbled through the reaction mixture over 10 minutes and the contents were transferred to a separatory funnel. The organic layer was separated, washed with brine (2 × 20 m), dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (using DCM and MeOH) to give the title compound (0 0.1 g) was obtained. The holding time is 3.09 minutes. YMC S5 Combiscreen 4.6 x 50 mm (4-minute gradient). Solvent A is 10% MeOH, 90% water and 0.2% phosphoric acid. Solvent B is 90% MeOH, 10% water and 0.2% phosphoric acid.

実施例３７ｂは、実施例３７ａに記載するのと同様な方法で、４−[(５Ｒ,９Ｓ)−３−(３,５−ジクロロフェニル)−１−メチル−２,４−ジオキソ−１,３,７−トリアザスピロ[４.４]ノナ−９−イル]ベンゾニトリル（０．１ｇ、０．２４ｍｍｏｌ）（実施例１５ｂ）から出発して、製造した。収量は０．０９１ｇである。保持時間は３．６８分である。YMC S5 ODS 4.6 × 50 mm（４分間の勾配）。溶媒Ａは、１０％ＭｅＯＨ、９０％水および０．２％リン酸である。溶媒Ｂは、９０％ＭｅＯＨ、１０％水および０．２％リン酸である。 Example 37b
5-[(5R, 9S) -9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] Nona-7-ylmethyl] -thiophene-3-carboxylic acid

Example 37b is prepared in a manner similar to that described in Example 37a, with 4-[(5R, 9S) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3 , 7-Triazaspiro [4.4] non-9-yl] benzonitrile (0.1 g, 0.24 mmol) (Example 15b). Yield is 0.091 g. The retention time is 3.68 minutes. YMC S5 ODS 4.6 x 50 mm (4-minute gradient). Solvent A is 10% MeOH, 90% water and 0.2% phosphoric acid. Solvent B is 90% MeOH, 10% water and 0.2% phosphoric acid.

式（Ｉａｃ）（式中、Ｒ_９は表４Ａに示す基を有する）を有する化合物を、実施例３７と同じ方法を用いて、実施例１５および適当なアルデヒドまたはケトンから出発して、製造した。

Examples 38-48

A compound having the formula (Iac) (wherein R ₉ has the groups shown in Table 4A) was prepared using the same method as Example 37, starting from Example 15 and the appropriate aldehyde or ketone. .

実施例１４と同じ方法を用いて、実施例１２（１００ｍｇ、０．２ｍｍｏｌ）をヨウ化エチル（２５μＬ、０．３１ｍｍｏｌ）と反応させることによって、白色固体の上記標題化合物（７０ｍｇ、イソプロピルエーテルからの結晶化後ではｍｐ＝２１６℃）を得た。¹H NMR (CDCl₃)：7.61 (2H, d, J = 8.3 Hz), 7.25-7.4 (8H, m), 6.67 (2H, d, J = 1.5 Hz), 3.5-4 (5H, m), 3.25-3.35 (2H, m), 2.95-3.2 (2H, m), 1.48 (3H, t, J = 7.2 Hz)。 Example 49
4-[(5S ^* , 9R ^* )-7-benzyl-3- (3,5-dichlorophenyl) -1-ethyl-2,4-dioxo-1,3,7-triazaspiro [4.4] nona-9 -Yl] benzonitrile

Using the same method as Example 14, Example 12 (100 mg, 0.2 mmol) was reacted with ethyl iodide (25 μL, 0.31 mmol) to give the title compound (70 mg, from isopropyl ether as a white solid). After crystallization, mp = 216 ° C.) was obtained. ¹ H NMR (CDCl ₃ ): 7.61 (2H, d, J = 8.3 Hz), 7.25-7.4 (8H, m), 6.67 (2H, d, J = 1.5 Hz), 3.5-4 (5H, m), 3.25-3.35 (2H, m), 2.95-3.2 (2H, m), 1.48 (3H, t, J = 7.2 Hz).

実施例１５に記載の方法を用いて、実施例４９（３．５ｇ、６．７４ｍｍｏｌ）をクロロギ酸１−クロロエチル（７．３ｍＬ、６６．９ｍｍｏｌ）と反応させて、アモルファス白色固体の上記標題化合物（１．８ｇ）を得た。¹H NMR (CDCl₃)：7.63 (2H, d, J =8.3 Hz), 7.25-7.35 (3H, m), 6.73 (2H, d, J = 1.5 Hz), 3.35-3.85 (7H, m), 1.17 (1H, br s), 1.45 (3H, t, J =7.1 Hz)。 Example 50
4-[(5S ^* , 9R ^* )-3- (3,5-dichlorophenyl) -1-ethyl-2,4-dioxo-1,3,7-triazaspiro [4.4] non-9-yl] benzo Nitrile

Using the method described in Example 15, Example 49 (3.5 g, 6.74 mmol) was reacted with 1-chloroethyl chloroformate (7.3 mL, 66.9 mmol) to give the title compound as an amorphous white solid. (1.8 g) was obtained. ¹ H NMR (CDCl ₃ ): 7.63 (2H, d, J = 8.3 Hz), 7.25-7.35 (3H, m), 6.73 (2H, d, J = 1.5 Hz), 3.35-3.85 (7H, m), 1.17 (1H, br s), 1.45 (3H, t, J = 7.1 Hz).

実施例１５に記載の方法を用いて、実施例１２（５ｇ、１０．１７ｍｍｏｌ）をクロロギ酸１−クロロエチル（１１．１ｍＬ、１０１．７ｍｍｏｌ）と反応させて、白色結晶の上記標題化合物（２ｇ）（ｍＰ＝１９８℃）を得た。¹H NMR (DMSO-d₆)：9.08 (1H, brs), 7.84 (2H, d, J = 8.2 Hz), 7.61 (1H, m), 7.45 (2H, d, J = 8.2 Hz), 6.79 (2H, d, J = 1.9 Hz), 3.1-3.85 (5H, m)。 Example 51
4-[(5S ^* , 9R ^* )-3- (3,5-dichlorophenyl) -2,4-dioxo-1,3,7-triazaspiro [4.4] non-9-yl] benzonitrile

Using the method described in Example 15, Example 12 (5 g, 10.17 mmol) was reacted with 1-chloroethyl chloroformate (11.1 mL, 101.7 mmol) to give the title compound (2 g) as white crystals. (MP = 198 ° C.) was obtained. ¹ H NMR (DMSO-d ₆ ): 9.08 (1H, brs), 7.84 (2H, d, J = 8.2 Hz), 7.61 (1H, m), 7.45 (2H, d, J = 8.2 Hz), 6.79 ( 2H, d, J = 1.9 Hz), 3.1-3.85 (5H, m).

実施例３７に記載する方法を用いて、５−ホルミル−３−チオフェンカルボン酸（４０ｍｇ、０．２６ｍｍｏｌ）を実施例５０（１００ｍｇ、０．２３ｍｍｏｌ）と反応させることによって、ＭｅＯＨから結晶化後に、白色固体の上記標題化合物（９３ｍｇ）（ｍｐ＝１８２℃）を得た。 Example 52
5-[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-ethyl-2,4-dioxo-1,3,7-triazaspiro [4. 4] Nona-7-ylmethyl] thiophene-3-carboxylic acid

After crystallization from MeOH by reacting 5-formyl-3-thiophenecarboxylic acid (40 mg, 0.26 mmol) with Example 50 (100 mg, 0.23 mmol) using the method described in Example 37. The title compound (93 mg) (mp = 182 ° C.) was obtained as a white solid.

実施例３７に記載する方法を用いて、５−ホルミル−３−チオフェンカルボン酸（４３ｍｇ、０．２７ｍｍｏｌ）を実施例５１（１００ｍｇ、０．２５ｍｍｏｌ）と反応させることによって、白色固体の上記標題化合物（９２ｍｇ）（ｍｐ＝２６０℃）を得た。 Example 53
5-[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -2,4-dioxo-1,3,7-triazaspiro [4.4] nona 7-ylmethyl] thiophene-3-carboxylic acid

Using the method described in Example 37, 5-formyl-3-thiophenecarboxylic acid (43 mg, 0.27 mmol) was reacted with Example 51 (100 mg, 0.25 mmol) to give the title compound as a white solid. (92 mg) (mp = 260 ° C.) was obtained.

実施例５０（１００ｍｇ、０．２３ｍｍｏｌ）および３−(クロロスルホニル)安息香酸（５７ｍｇ、０．２６ｍｍｏｌ）のＴＨＦ（５ｍＬ）混合物に、ＤＩＥＡ（４５μＬ、０．２６ｍｍｏｌ）を室温で加えた。該反応混合物を室温で２４時間撹拌し、次いで真空下で濃縮した。該残渣をＥｔＯＡｃおよび水の間で分配した。該ｐＨを、ｐＨ＝２にまで調節した。該水相をＥｔＯＡｃを用いて２回抽出した。該有機層を合わせてブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥し、そして濃縮した。該得た固体をシリカゲルクロマトグラフィー精製（ＤＣＭ／ＭｅＯＨ（８０／２０）を使用）を行なって、上記標題化合物（６３ｍｇ、ｍｐ＝１４５℃）を得た。¹H NMR (CDCl₃)：8.63 (1H, s), 8.41 (1H, d, J = 7.5 Hz), 8.17 (1H, d, J = 7.4 Hz), 7.77 (1H, t, J = 7.7 Hz), 7.62 (2H, d, J = 7.7 Hz), 7.18-7.26 (3H, m), 6.60 (2H, s), 3.4-4.2 (7H, m), 1.45 (3H, t, J =6.8 Hz)。 Example 54
3-[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-ethyl-2,4-dioxo-1,3,7-triazaspiro [4. 4] Nonane-7-sulfonyl] benzoic acid

To a mixture of Example 50 (100 mg, 0.23 mmol) and 3- (chlorosulfonyl) benzoic acid (57 mg, 0.26 mmol) in THF (5 mL) was added DIEA (45 μL, 0.26 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 hours and then concentrated under vacuum. The residue was partitioned between EtOAc and water. The pH was adjusted to pH = 2. The aqueous phase was extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated. The obtained solid was purified by silica gel chromatography (using DCM / MeOH (80/20)) to give the title compound (63 mg, mp = 145 ° C.). ¹ H NMR (CDCl ₃ ): 8.63 (1H, s), 8.41 (1H, d, J = 7.5 Hz), 8.17 (1H, d, J = 7.4 Hz), 7.77 (1H, t, J = 7.7 Hz) 7.62 (2H, d, J = 7.7 Hz), 7.18-7.26 (3H, m), 6.60 (2H, s), 3.4-4.2 (7H, m), 1.45 (3H, t, J = 6.8 Hz).

実施例５４の方法を用いて、実施例５１（１００ｍｇ、０．２５ｍｍｏｌ）を、ＴＨＦ（５ｍＬ）中、ＤＩＥＡ（４８μＬ、０．２７ｍｍｏｌ）の存在下、室温で３−(クロロスルホニル)安息香酸（６１ｍｇ、０．２７ｍｍｏｌ）と反応させて、上記標題化合物（８４ｍｇ、ｍｐ＝１５０℃）を得た。¹H NMR (DMSO-d₆)：9.14 (1H, br s), 8.35 (1H, s), 8.29 (1H, d, J = 7.7 Hz), 8.18 (1H, d, J = 7.7 Hz), 7.83 (3H, m), 7.61 (1H, s), 7.38 (2H, d, J = 8.1 Hz), 6.69 (2H, d, J = 1.5 Hz), 3.65-4.05 (4H, m), 3.5-3.6 (1H, m)。 Example 55
3-[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -2,4-dioxo-1,3,7-triazaspiro [4.4] nonane 7-sulfonyl] benzoic acid

Using the method of Example 54, Example 51 (100 mg, 0.25 mmol) was dissolved in 3- (chlorosulfonyl) benzoic acid (THF) at room temperature in the presence of DIEA (48 μL, 0.27 mmol) in THF (5 mL). 61 mg, 0.27 mmol) to give the title compound (84 mg, mp = 150 ° C.). ¹ H NMR (DMSO-d ₆ ): 9.14 (1H, br s), 8.35 (1H, s), 8.29 (1H, d, J = 7.7 Hz), 8.18 (1H, d, J = 7.7 Hz), 7.83 (3H, m), 7.61 (1H, s), 7.38 (2H, d, J = 8.1 Hz), 6.69 (2H, d, J = 1.5 Hz), 3.65-4.05 (4H, m), 3.5-3.6 ( 1H, m).

実施例１４に記載の方法を用いて、実施例１２（１００ｍｇ、０．２ｍｍｏｌ）を、ＤＭＦ（１ｍＬ）中でＮａＨ（油中６０％、１２ｍｇ、０．３ｍｍｏｌ）を用いて脱プロトン化し、そしてこのものを４−ブロモ酪酸エチル（４４μＬ、０．３ｍｍｏｌ）と反応させて上記標題化合物を得て、このものをＥｔ_２Ｏ／ＨＣｌガス（８６ｍｇ）中で沈降させることによって、その塩酸塩に変換した。ＬＣマス：保持時間＝２．２７分、Ｍ_ｏｂｓ＝604 (M-1) (LCMS条件：LC Micromass platform (APCI＋, DAD (210-400 nm))、カラム：TSK gel Super ODS 4.6 mm ID×5 cm、流速：2.75 mL／分、勾配：１００％溶出液Ａ〜１００％溶出液Ｂを２分間および１００％溶出液Ｂのプラトーを１分間。溶出液ＡはＨ_２Ｏ（０．０５％ＴＦＡ）であり、溶出液ＢはＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡ（８０／２０／０．０５）である。 Example 56
4-[(5S ^* , 9R ^* )-7-benzyl-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -2,4-dioxo-1,3,7-triazaspiro [4. 4] Non-1-yl] butyric acid ethyl ester hydrochloride

Using the method described in Example 14, Example 12 (100 mg, 0.2 mmol) was deprotonated with NaH (60% in oil, 12 mg, 0.3 mmol) in DMF (1 mL) and This was reacted with ethyl 4-bromobutyrate (44 μL, 0.3 mmol) to give the title compound, which was converted to its hydrochloride salt by precipitation in Et ₂ O / HCl gas (86 mg). did. LC mass: Retention time = 2.27 minutes, M _obs = 604 (M-1) (LCMS condition: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 2.75 mL / min, gradient: 100% eluent A to 100% eluent B for 2 minutes and 100% eluent B plateau for 1 minute, eluent A is H ₂ O (0.05% TFA) Eluent B is CH ₃ CN / H ₂ O / TFA (80/20 / 0.05).

Examples 57-58
Using the method described in Example 56, the following two examples were prepared by reacting Example 12 (100 mg) with ethyl 5-bromo-ethyl valerate and ethyl 6-bromo-caproate, respectively.

収量は５５ｍｇである。ＬＣマス：保持時間＝２．４０分、Ｍ_ｏｂｓ＝618 (M-1) (LCMS条件：LC Micromass platform (APCI＋, DAD (210-400 nm))、カラム：TSK gel Super ODS 4.6 mm ID×5 cm、流速：2.75 mL／分、勾配：１００％溶出液Ａ〜１００％溶出液Ｂを２分間および１００％溶出液Ｂのプラトーを１分間。溶出液ＡはＨ_２Ｏ（０．０５％ＴＦＡ）であり、溶出液ＢはＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡ（８０／２０／０．０５）である。 Example 57
5-[(5S ^* , 9R ^* )-7-benzyl-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -2,4-dioxo-1,3,7-triazaspiro [4. 4] Non-1-yl] pentanoic acid ethyl ester hydrochloride

Yield is 55 mg. LC mass: Retention time = 2.40 min, M _obs = 618 (M-1) (LCMS conditions: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 2.75 mL / min, gradient: 100% eluent A to 100% eluent B for 2 minutes and 100% eluent B plateau for 1 minute, eluent A is H ₂ O (0.05% TFA) Eluent B is CH ₃ CN / H ₂ O / TFA (80/20 / 0.05).

収量は５４ｍｇである。ＬＣマス：保持時間＝２．２９分、Ｍ_ｏｂｓ＝632 (M-1) (LCMS条件：LC Micromass platform (APCI＋, DAD (210-400 nm))、カラム：TSK gel Super ODS 4.6 mm ID × 5 cm、流速：2.75 mL／分、勾配：１００％溶出液Ａ〜１００％溶出液Ｂを２分間および１００％溶出液Ｂのプラトーを１分間。溶出液ＡはＨ_２Ｏ（０．０５％ＴＦＡ）であり、溶出液ＢはＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡ（８０／２０／０．０５）である。 Example 58
6-[(5S ^* , 9R ^* )-7-benzyl-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -2,4-dioxo-1,3,7-triazaspiro [4. 4] Non-1-yl] hexanoic acid ethyl ester hydrochloride

Yield is 54 mg. LC mass: Retention time = 2.29 min, M _obs = 632 (M-1) (LCMS condition: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 2.75 mL / min, gradient: 100% eluent A to 100% eluent B for 2 minutes and 100% eluent B plateau for 1 minute, eluent A is H ₂ O (0.05% TFA) Eluent B is CH ₃ CN / H ₂ O / TFA (80/20 / 0.05).

実施例５９［ｅが１である、式（Ｉａｆ）の化合物］を製造するために、ＬｉＯＨ（１Ｎ、６００μＬ）を、実施例５６（６０．３ｍｇ、０．１ｍｍｏｌ）のＴＨＦ（２．５ｍＬ）懸濁液に加えた。該溶液を５０℃で３時間加熱した。真空下で濃縮後に、該生成物を水に溶かし、このものをＳＯ_２ガスをバブルすることによって酸性とした。該溶液から沈降した実施例５９をろ過によって集め、そして乾燥した。収量は１７ｍｇであり、ｍｐ＝１４８℃。実施例６０（ｅ＝２）および実施例６１（ｅ＝３）を、同じ方法を用いて、それぞれ実施例５７および５８から出発して製造した。実施例６０：（３５．４ｍｇ）。収量：２２ｍｇ、白色結晶、ｍｐ＝２５０℃；実施例６１：（３２．５ｍｇ）。収量：１７．４ｍｇ。¹H NMR (CDCl₃)：7.61 (2H, d, J = 8 Hz), 7.25-7.40 (8H, m), 6.64 (2H, s), 3.8-4.0 (3H, m), 3.5-3.8 (2H, m), 3.3-3.5 (2H, m), 3-3.3 (2H, m), 2.3-2.45 (2H, m), 1.7-1.9 (4H, m), 1.45-1.55 (2H, m)。 Examples 59-61
ω-[(5S ^* , 9R ^* )-7-benzyl-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -2,4-dioxo-1,3,7-triazaspiro [4. 4] Non-1-yl] alkanoic acid

To prepare Example 59 [compound of formula (Iaf) where e is 1], LiOH (1N, 600 μL) was added to Example 56 (60.3 mg, 0.1 mmol) in THF (2.5 mL). Added to suspension. The solution was heated at 50 ° C. for 3 hours. After concentration in vacuo, the product dissolved in water, the thing was acidified by bubbling SO ₂ gas. Example 59 that precipitated from the solution was collected by filtration and dried. Yield 17 mg, mp = 148 ° C. Example 60 (e = 2) and Example 61 (e = 3) were prepared starting from Examples 57 and 58, respectively, using the same method. Example 60: (35.4 mg). Yield: 22 mg, white crystals, mp = 250 ° C .; Example 61: (32.5 mg). Yield: 17.4 mg. ¹ H NMR (CDCl ₃ ): 7.61 (2H, d, J = 8 Hz), 7.25-7.40 (8H, m), 6.64 (2H, s), 3.8-4.0 (3H, m), 3.5-3.8 (2H m), 3.3-3.5 (2H, m), 3-3.3 (2H, m), 2.3-2.45 (2H, m), 1.7-1.9 (4H, m), 1.45-1.55 (2H, m).

実施例１５（１００ｍｇ、０．２４ｍｍｏｌ）、ブロモ酢酸エチル（２９μＬ、０．２６ｍｍｏｌ）およびＫ_２ＣＯ_３（３６．６ｍｇ、０．２６ｍｍｏｌ）のトルエン（２ｍＬ）混合物を、１００℃まで５時間加熱した。室温まで冷却後に、該沈降物（未反応の出発物質）を、ろ過によって除去した。該ろ液を濃縮し、そしてシリカゲルクロマトグラフィー（溶出液はＤＣＭ、次いでアセトンである）によって精製して、油状物の上記標題化合物（４７．２ｍｇ）を得た。¹H NMR (CDCl₃)：7.63 (2H, d, J = 8.3 Hz), 7.25-7.30 (3H, m), 6.68 (2H, d, J = 1.5 Hz), 4.23 (2H, q, J = 7.1 Hz), 3.89 (1H, dd, J₁ = 11.7 Hz , J₂ = 6.3 Hz), 3.55-3.65 (2H, m), 3.3-3.5 (3H, m), 3.26 (3H, s), 3.05 (1H, d, J = 10.8 Hz), 1.31 (3H, t, J = 7.1 Hz)。 Example 62
[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] Non-7-yl] acetic acid ethyl ester

A mixture of Example 15 (100 mg, 0.24 mmol), ethyl bromoacetate (29 μL, 0.26 mmol) and K ₂ CO ₃ (36.6 mg, 0.26 mmol) in toluene (2 mL) was heated to 100 ° C. for 5 hours. . After cooling to room temperature, the precipitate (unreacted starting material) was removed by filtration. The filtrate was concentrated and purified by silica gel chromatography (eluent is DCM then acetone) to give the title compound (47.2 mg) as an oil. ¹ H NMR (CDCl ₃ ): 7.63 (2H, d, J = 8.3 Hz), 7.25-7.30 (3H, m), 6.68 (2H, d, J = 1.5 Hz), 4.23 (2H, q, J = 7.1 Hz), 3.89 (1H, dd, J ₁ = 11.7 Hz, J ₂ = 6.3 Hz), 3.55-3.65 (2H, m), 3.3-3.5 (3H, m), 3.26 (3H, s), 3.05 (1H , d, J = 10.8 Hz), 1.31 (3H, t, J = 7.1 Hz).

実施例１５（２ｇ、４．８１ｍｍｏｌ）、ブロモ酢酸ｔｅｒｔ−ブチル（２．４ｍＬ、１６．３ｍｍｏｌ）およびＫ_２ＣＯ_３（２．４ｇ、１７．４ｍｍｏｌ）のジオキサン（４０ｍＬ）混合物を２４時間還流した。室温まで冷却後に、該溶液を濃縮し、そしてＤＣＭ／水の間で分配した。該水相をＤＣＭを用いて２回抽出した。該有機層を合わせてブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥し、そして濃縮して油状物を得て、このものをシリカゲルクロマトグラフィー（溶出液は、ＤＣＭ／アセトンの９５／５である）によって精製して、アモルファス固体の上記標題化合物（１．５６ｇ）を得た。¹H NMR (CDCl₃)：7.62 (2H, d, J = 8.3 Hz), 7.25-7.30 (3H, m), 6.67 (2H, d, J = 1.5 Hz), 3.80-3.95 (1H, dd), 3.55-3.65 (2H, m), 3.3-3.5 (3H, m), 3.26 (3H, s), 3.02 (1H, d, J = 10.9 Hz), 1.50 (9H, s)。 Example 63
[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] Nona-7-yl] acetic acid tert-butyl ester

A mixture of Example 15 (2 g, 4.81 mmol), tert-butyl bromoacetate (2.4 mL, 16.3 mmol) and K ₂ CO ₃ (2.4 g, 17.4 mmol) in dioxane (40 mL) was refluxed for 24 hours. . After cooling to room temperature, the solution was concentrated and partitioned between DCM / water. The aqueous phase was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to give an oil that was chromatographed on silica gel (eluent is 95/5 DCM / acetone). To give the title compound (1.56 g) as an amorphous solid. ¹ H NMR (CDCl ₃ ): 7.62 (2H, d, J = 8.3 Hz), 7.25-7.30 (3H, m), 6.67 (2H, d, J = 1.5 Hz), 3.80-3.95 (1H, dd), 3.55-3.65 (2H, m), 3.3-3.5 (3H, m), 3.26 (3H, s), 3.02 (1H, d, J = 10.9 Hz), 1.50 (9H, s).

トリフルオロ酢酸（４．８ｍＬ、５９ｍｍｏｌ）を、実施例６３（１．５６ｇ、２．９５ｍｍｏｌ）のＤＣＭ（４０ｍＬ）溶液に加えた。該溶液を３時間還流した。次いで、真空下で濃縮し、そしてＥｔＯＡｃ／ＮＨ_４ＯＨ水溶液の間で分配した。該水溶液をＳＯ_２を用いてｐＨ＝２にまで酸性とした。該白色沈降物をろ過によって分離した。該水相をＤＣＭを用いて抽出し、濃縮して白色結晶を得て、このものを該沈降した固体と合わせて、乾燥後に、上記標題化合物（１．０４ｇ）（ｍｐ＝２２０℃）を得た。 Example 64
[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] Non-7-yl] acetic acid

Trifluoroacetic acid (4.8 mL, 59 mmol) was added to a solution of Example 63 (1.56 g, 2.95 mmol) in DCM (40 mL). The solution was refluxed for 3 hours. It was then concentrated in vacuo and partitioned between EtOAc / NH ₄ OH aqueous solution. The aqueous solution was acidified to pH = 2 with SO _2. The white precipitate was separated by filtration. The aqueous phase was extracted with DCM and concentrated to give white crystals which were combined with the precipitated solid to give the title compound (1.04 g) (mp = 220 ° C.) after drying. It was.

実施例１４に記載の方法を用いて、実施例１３（５．４５ｇ、１０ｍｍｏｌ）をヨウ化メチル（０．９３ｍＬ、１４．９ｍｍｏｌ）と反応させて、白色固体の上記標題化合物（４．１５ｇ）（ｍｐ＝２０４℃）を得た。 Example 65
(5S ^* , 9R ^* )-7-benzyl-9- (4-bromophenyl) -3- (3,5-dichlorophenyl) -1-methyl-1,3,7-triazaspiro [4.4] nonane-2 , 4-dione

Using the method described in Example 14, Example 13 (5.45 g, 10 mmol) was reacted with methyl iodide (0.93 mL, 14.9 mmol) to give the above title compound (4.15 g) as a white solid. (Mp = 204 ° C.) was obtained.

実施例６５（２ｇ、３．５８ｍｍｏｌ）、５−トリメチルスタニル−ピリミジン（１．３ｇ、５．３５ｍｍｏｌ、このものは特許ＷＯ９５／０６６３６号に従って製造する）およびテトラキス(トリフェニルホスフィン)パラジウム(０)（６２０ｍｇ、０．５４ｍｍｏｌ）のトルエン（５０ｍＬ）混合物を、窒素雰囲気下、１０時間還流した。室温まで冷却後に、該不溶性物質をろ過して除き、そしてこのものをトルエンで２回洗浄した。該トルエン相を真空下で濃縮した。得られた橙色油状物（３．１ｇ）をシリカゲルクロマトグラフィー（溶出液は、ＥｔＯＡｃである）精製を行なって、ＭｅＯＨから結晶化後に、白色固体の上記標題化合物（４３０ｍｇ）（ｍｐ＝２２８℃）を得た。 Example 66
(5S ^* , 9R ^* )-7-benzyl-3- (3,5-dichlorophenyl) -1-methyl-9- (4-pyrimidin-5-yl-phenyl) -1,3,7-triazaspiro [4. 4] Nonane-2,4-dione

Example 65 (2 g, 3.58 mmol), 5-trimethylstannyl-pyrimidine (1.3 g, 5.35 mmol, which is prepared according to patent WO 95/06636) and tetrakis (triphenylphosphine) palladium (0) A toluene (50 mL) mixture of (620 mg, 0.54 mmol) was refluxed for 10 hours under a nitrogen atmosphere. After cooling to room temperature, the insoluble material was filtered off and it was washed twice with toluene. The toluene phase was concentrated under vacuum. The resulting orange oil (3.1 g) was purified by silica gel chromatography (eluent is EtOAc) and after crystallization from MeOH, the title compound (430 mg) as a white solid (mp = 228 ° C.) Got.

実施例１５に記載の方法を用いて、実施例６６（３５８ｍｇ、０．６４ｍｍｏｌ）をＤＣＭ（３ｍＬ）中で、クロロギ酸１−クロロエチル（０．２８ｍＬ、２．６ｍｍｏｌ）と反応させて、アモルファス固体の上記標題化合物（８８ｍｇ）を得た。¹H NMR (CDCl₃)：9.22 (1H, s), 8.94 (2H, s), 7.58 (2H, d, J = 8.2 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.21 (1H, m), 6.66 (2H, d, J = 1.6 Hz), 3.3-3.9 (5H, m), 3.23 (3H, s), 2.63 (1H, br s)。 Example 67
(5S ^* , 9R ^* )-3- (3,5-dichlorophenyl) -1-methyl-9- (4-pyrimidin-5-yl-phenyl) -1,3,7-triazaspiro [4.4] nonane 2,4-dione

Example 66 (358 mg, 0.64 mmol) was reacted with 1-chloroethyl chloroformate (0.28 mL, 2.6 mmol) in DCM (3 mL) using the method described in Example 15 to obtain an amorphous solid. Of the title compound (88 mg) was obtained. ¹ H NMR (CDCl ₃ ): 9.22 (1H, s), 8.94 (2H, s), 7.58 (2H, d, J = 8.2 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.21 (1H, m), 6.66 (2H, d, J = 1.6 Hz), 3.3-3.9 (5H, m), 3.23 (3H, s), 2.63 (1H, br s).

実施例３７に記載の方法を用いて、実施例６７（３７．３ｍｇ、０．０８ｍｍｏｌ）を、ＤＣＥ（３ｍＬ）中で５−ホルミル−３−チオフェンカルボン酸（１５ｍｇ、０．０９６ｍｍｏｌ）と反応させて、アモルファス固体の上記標題化合物（４３ｍｇ）を得た。¹H NMR (CDCl₃)：9.23 (1H, s), 8.96 (2H, s), 8.16 (1H, s), 7.45-7.65 (3H, m), 7.29 (2H, d, J = 8.1 Hz), 7.20 (1H, m), 6.65 (2H, d, J = 1.4 Hz), 3.9-4.2 (3H, m), 3.2-3.5 (3H, m), 3.23 (3H, s), 3.10 (1H, d, J = 11.1 Hz)。 Example 68
5-[(5S ^* , 9R ^* )-3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-9- (4-pyrimidin-5-yl-phenyl) -1,3,7 -Triazaspiro [4.4] non-7-ylmethyl] thiophene-3-carboxylic acid

Example 67 (37.3 mg, 0.08 mmol) was reacted with 5-formyl-3-thiophenecarboxylic acid (15 mg, 0.096 mmol) in DCE (3 mL) using the method described in Example 37. The above title compound (43 mg) was obtained as an amorphous solid. ¹ H NMR (CDCl ₃ ): 9.23 (1H, s), 8.96 (2H, s), 8.16 (1H, s), 7.45-7.65 (3H, m), 7.29 (2H, d, J = 8.1 Hz), 7.20 (1H, m), 6.65 (2H, d, J = 1.4 Hz), 3.9-4.2 (3H, m), 3.2-3.5 (3H, m), 3.23 (3H, s), 3.10 (1H, d, J = 11.1 Hz).

実施例６７（４９．７ｍｇ、０．１１ｍｍｏｌ）、２−ヨードプロパン（２６μＬ、０．２６ｍｍｏｌ）およびＫ_２ＣＯ_３（３６ｍｇ、０．２６ｍｍｏｌ）の混合物を、アセトニトリル（２ｍＬ）中、８０℃で２５時間加熱した。室温まで冷却後に、該不溶性塩を除去し、そして該ろ液を乾固するまで濃縮した。該残渣をＤＣＭ／水の間で分配した。該有機相を真空下で濃縮し、そしてシリカゲルクロマトグラフィー精製（溶出液はＤＣＭ／ＭｅＯＨの９５／５である）を行なって、アモルファス白色固体の上記標題化合物（３８．１ｍｇ）を得た。¹H NMR (CDCl₃)：9.21 (1H, s), 8.92 (2H, s), 7.56 (2H, d, J = 8.0 Hz), 7.33 (2H, d, J = 8.0 Hz), 7.20 (1H, m), 6.61 (2H, d, J = 1.5 Hz), 3.90 (1H, dd, J₁ = 12 Hz , J₂ = 6 Hz), 3.4-3.5 (2H, m), 3.2-3.4 (1H, m), 3.28 (3H, s), 3.09 (1H, d, J = 11 Hz), 2.79 (1H, m), 1.23 (6H, m)。 Example 69
(5S ^* , 9R ^* )-3- (3,5-dichlorophenyl) -1-methyl-7- (1-methylethyl) -9- (4-pyrimidin-5-yl-phenyl) -1,3,7 -Triazaspiro [4.4] nonane-2,4-dione

A mixture of Example 67 (49.7 mg, 0.11 mmol), 2-iodopropane (26 μL, 0.26 mmol) and K ₂ CO ₃ (36 mg, 0.26 mmol) was added in acetonitrile (2 mL) at 80 ° C. Heated for hours. After cooling to room temperature, the insoluble salt was removed and the filtrate was concentrated to dryness. The residue was partitioned between DCM / water. The organic phase was concentrated in vacuo and subjected to silica gel chromatography purification (eluent is 95/5 DCM / MeOH) to give the title compound (38.1 mg) as an amorphous white solid. ¹ H NMR (CDCl ₃ ): 9.21 (1H, s), 8.92 (2H, s), 7.56 (2H, d, J = 8.0 Hz), 7.33 (2H, d, J = 8.0 Hz), 7.20 (1H, m), 6.61 (2H, d, J = 1.5 Hz), 3.90 (1H, dd, J ₁ = 12 Hz, J ₂ = 6 Hz), 3.4-3.5 (2H, m), 3.2-3.4 (1H, m ), 3.28 (3H, s), 3.09 (1H, d, J = 11 Hz), 2.79 (1H, m), 1.23 (6H, m).

式（Ｉａｅ）（式中、Ｒ_９は表４Ｂ中に示す基を有する）を有する化合物を、実施例６９と同じ方法を用いて、実施例１５および適当なヨード化合物から出発して、製造した。

Examples 70-74

A compound having the formula (Iae) (wherein R ₉ has the groups shown in Table 4B) was prepared using the same method as Example 69, starting from Example 15 and the appropriate iodo compound. .

ＮａＯＨ（２ｍＬ、１Ｎ）を、実施例７３（１９９ｍｇ、０．４８ｍｍｏｌ）のＴＨＦ（２ｍＬ）溶液に加えた。室温で３時間後に、該溶液をＳＯ_２を用いて酸性とし、そして真空下で濃縮した。該得られた固体を水およびＥｔＯＡｃの間で分配した。該有機層をＮａ_２ＳＯ_４で乾燥し、そして濃縮して上記標題化合物を得て、このものをＭｅＯＨから結晶化した（２３ｍｇ）（ｍｐ＝２２８℃）。 Example 75
4-[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4. 4] Nona-7-yl] butyric acid

NaOH (2 mL, 1N) was added to a solution of Example 73 (199 mg, 0.48 mmol) in THF (2 mL). After 3 hours at room temperature, the solution was acidified with SO ₂ and concentrated in vacuo. The resulting solid was partitioned between water and EtOAc. The organic layer was dried over Na ₂ SO ₄ and concentrated to give the title compound, which was crystallized from MeOH (23 mg) (mp = 228 ° C.).

実施例７５と同じ方法を用いて、実施例７４（１９０ｍｇ、０．３６ｍｍｏｌ）を上記標題化合物（１５２ｍｇ）に変換した。白色固体、ｍｐ＝２４０℃。 Example 76
5-[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4. 4] Nona-7-yl] pentanoic acid

Using the same method as Example 75, Example 74 (190 mg, 0.36 mmol) was converted to the title compound (152 mg). White solid, mp = 240 ° C.

クロロギ酸イソブチル（２７μＬ、０．２１ｍｍｏｌ）を、ＤＣＭ（４ｍＬ）中、実施例６４（９０ｍｇ、０．１９ｍｍｏｌ）およびＮ−メチルモルホリン（２３μＬ、０．２ｍｍｏｌ）の冷（５℃）懸濁液に加えた。１時間後に、アンモニア（４２０μＬ、０．５Ｍジオキサン溶液、０．２１ｍｍｏｌ）を加えた。５℃で１時間およびＲＴで３時間後に、水（２ｍＬ）を加えた。該有機層を分離し、そして水相をＤＣＭを用いて抽出した。該有機層を合わせて真空下で濃縮し、そして得られた物質をシリカゲルクロマトグラフィー(溶出液はＤＣＭ／ＭｅＯＨの９５／５である）によって精製して、固体の上記標題化合物（４９．６ｍｇ）を得た。¹H NMR (CDCl₃)：7.64 (2H, d, J = 8.2 Hz), 7.25-7.30 (3H, m), 6.84 (1H, br s), 6.65 (2H, d, J = 1.5 Hz), 6.18 (1H, br s), 3.87 (1H, t), 3.4-3.5 (5H, m), 3.24 (3H, s), 3.15 (1H, d, J = 10.9 Hz)。 Example 77
[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] Non-7-yl] acetamide

Isobutyl chloroformate (27 μL, 0.21 mmol) was added to a cold (5 ° C.) suspension of Example 64 (90 mg, 0.19 mmol) and N-methylmorpholine (23 μL, 0.2 mmol) in DCM (4 mL). added. After 1 hour, ammonia (420 μL, 0.5 M dioxane solution, 0.21 mmol) was added. After 1 hour at 5 ° C. and 3 hours at RT, water (2 mL) was added. The organic layer was separated and the aqueous phase was extracted with DCM. The organic layers were combined and concentrated in vacuo and the resulting material was purified by silica gel chromatography (eluent is 95/5 DCM / MeOH) to give the title compound (49.6 mg) as a solid. Got. ¹ H NMR (CDCl ₃ ): 7.64 (2H, d, J = 8.2 Hz), 7.25-7.30 (3H, m), 6.84 (1H, br s), 6.65 (2H, d, J = 1.5 Hz), 6.18 (1H, br s), 3.87 (1H, t), 3.4-3.5 (5H, m), 3.24 (3H, s), 3.15 (1H, d, J = 10.9 Hz).

Examples 78-79
The following examples were prepared using the experimental method described in Example 77.

実施例６４（９０ｍｇ、０．１９ｍｍｏｌ）およびメチルアミン（１０５μＬ、２Ｍ ＴＨＦ溶液、０．２１ｍｍｏｌ）を用いて、固体の上記標題化合物（４７．１ｍｇ）を得た。¹H NMR (CDCl₃)：7.64 (2H, d, J = 8.1 Hz), 7.27-7.31 (3H, m), 6.95 (1H, br s), 6.65 (2H, d, J = 1.3 Hz), 3.87 (1H, t), 3.35-3.5 (5H, m), 3.25 (3H, s), 3.16 (1H, d, J = 10.9 Hz), 2.89 (3H, d, J = 4.9 Hz)。 Example 78
[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] Nona-7-yl] -N-methylacetamide

Example 64 (90 mg, 0.19 mmol) and methylamine (105 μL, 2M in THF, 0.21 mmol) were used to give the title compound (47.1 mg) as a solid. ¹ H NMR (CDCl ₃ ): 7.64 (2H, d, J = 8.1 Hz), 7.27-7.31 (3H, m), 6.95 (1H, br s), 6.65 (2H, d, J = 1.3 Hz), 3.87 (1H, t), 3.35-3.5 (5H, m), 3.25 (3H, s), 3.16 (1H, d, J = 10.9 Hz), 2.89 (3H, d, J = 4.9 Hz).

実施例６４（９０ｍｇ、０．１９ｍｍｏｌ）およびジメチルアミン（１０５μＬ、２Ｍ ＴＨＦ溶液、０．２１ｍｍｏｌ）を用いて、固体の上記標題化合物（７８．８ｍｇ）を得た。¹H NMR (CDCl₃)：7.62 (2H, d, J = 8 Hz), 7.15-7.3 (3H, m), 6.68 (2H, d, J = 1.8 Hz), 3.92 (1H, dd, J₁ = 11.4 Hz , J₂ = 6.2 Hz), 3.6-3.75 (2H, m), 3.35-3.5 (3H, m), 3.26 (3H, s), 3.05 (3H, s), 2.99 (3H, s), 2.95-3.0 (1H, m)。 Example 79
[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] Non-7-yl] -N, N-dimethylacetamide

Example 64 (90 mg, 0.19 mmol) and dimethylamine (105 μL, 2M in THF, 0.21 mmol) were used to give the title compound (78.8 mg) as a solid. ¹ H NMR (CDCl ₃ ): 7.62 (2H, d, J = 8 Hz), 7.15-7.3 (3H, m), 6.68 (2H, d, J = 1.8 Hz), 3.92 (1H, dd, J ₁ = 11.4 Hz, J ₂ = 6.2 Hz), 3.6-3.75 (2H, m), 3.35-3.5 (3H, m), 3.26 (3H, s), 3.05 (3H, s), 2.99 (3H, s), 2.95 -3.0 (1H, m).

ＥＤＣＩ（８４ｍｇ、０．４４ｍｍｏｌ）を、実施例３７（１００ｍｇ、０．１８ｍｍｏｌ）、メタンスルホンアミド（３８ｍｇ、０．３８ｍｍｏｌ）、トリエチルアミン（６２μＬ、０．４３ｍｍｏｌ）および微量のＤＭＡＰのＤＣＭ（５ｍＬ）溶液に室温で加えた。４８時間後に水を加え、そして該混合物をＳＯ_２をバブルすることによって酸性とした。該有機層を分離し、そして該水相をＤＣＭを用いて２回抽出した。該有機層を合わせて、ブラインで洗浄し、そして真空下で濃縮した。得られた生成物をシリカゲルクロマトグラフィー精製を行なって、アモルファス固体の上記標題化合物（３８．９ｍｇ）および未反応の出発物質（５５．６ｍｇ）を得た。¹H NMR (CDCl₃)：8.04 (1H, s), 7.62 (2H, d, J = 8 Hz), 7.40 (1H, s), 7.25-7.3 (3H, m), 6.65 (2H, d, J = 1.5 Hz), 3.8-4.1 (3H, m), 3.86 (3H, s), 3.3-3.4 (2H, m), 3.3.25 (3H, s), 3.15-3.3 (1H, m), 3.01 (1H, d, J = 11 Hz)。 Example 80
N- {5-[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] Nona-7-ylmethyl] thiophene-3-carbonyl} methanesulfonamide

EDCI (84 mg, 0.44 mmol) was added to Example 37 (100 mg, 0.18 mmol), methanesulfonamide (38 mg, 0.38 mmol), triethylamine (62 μL, 0.43 mmol) and a trace amount of DMAP in DCM (5 mL). At room temperature. Water is added after 48 hours, and the mixture was acidified by bubbling SO _2. The organic layer was separated and the aqueous phase was extracted twice with DCM. The organic layers were combined, washed with brine and concentrated in vacuo. The resulting product was purified by silica gel chromatography to give the title compound (38.9 mg) as an amorphous solid and unreacted starting material (55.6 mg). ¹ H NMR (CDCl ₃ ): 8.04 (1H, s), 7.62 (2H, d, J = 8 Hz), 7.40 (1H, s), 7.25-7.3 (3H, m), 6.65 (2H, d, J = 1.5 Hz), 3.8-4.1 (3H, m), 3.86 (3H, s), 3.3-3.4 (2H, m), 3.3.25 (3H, s), 3.15-3.3 (1H, m), 3.01 ( 1H, d, J = 11 Hz).

実施例８０と同じ方法を用いて、実施例１８５（２００ｍｇ、０．３６ｍｍｏｌ）をメタンスルホンアミド（３８．１ｍｇ、０．４ｍｍｏｌ）と反応させることによって、上記標題化合物（６４ｍｇ）を得た。¹H NMR (CDCl₃)：7.86 (2H, d, J = 8.1 Hz), 7.63 (2H, d, J = 8 Hz), 7.55 (2H, d, J = 8 Hz), 7.25-7.3 (3H, m), 6.65 (2H, d, J = 1.3 Hz), 3.85-4.05 (3H, m), 3.2-3.45 (3H, m), 3.44 (3H, s), 3.24 (3H, s), 3.05 (1H, J = 11.1 Hz)。 Example 81
N- {4-[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] Nona-7-ylmethyl] benzoyl} methanesulfonamide

Using the same method as Example 80, Example 185 (200 mg, 0.36 mmol) was reacted with methanesulfonamide (38.1 mg, 0.4 mmol) to give the title compound (64 mg). ¹ H NMR (CDCl ₃ ): 7.86 (2H, d, J = 8.1 Hz), 7.63 (2H, d, J = 8 Hz), 7.55 (2H, d, J = 8 Hz), 7.25-7.3 (3H, m), 6.65 (2H, d, J = 1.3 Hz), 3.85-4.05 (3H, m), 3.2-3.45 (3H, m), 3.44 (3H, s), 3.24 (3H, s), 3.05 (1H , J = 11.1 Hz).

実施例１５（１００ｍｇ、０．２４ｍｍｏｌ）、Ｋ_２ＣＯ_３（３７ｍｇ、０．２７ｍｍｏｌ）および２−ブロモピリミジン（４２ｍｇ、０．２７ｍｍｏｌ）の混合物を、ＤＭＦ（１ｍＬ）中、１００℃で２０時間加熱した。室温まで冷却後に、該不溶性塩を除去し、そして該ろ液を水およびＥｔＯＡｃの間で分配した。該水相をＥｔＯＡｃを用いて２回抽出した。該有機相を合わせて水およびブラインで洗浄し、真空下で濃縮し、そしてシリカゲルクロマトグラフィー（溶出液はＤＣＭ／ＭｅＯＨの９５／５である）を用いて精製して、上記標題化合物（３６．１ｍｇ）を得た。ＭｅＯＨからの白色結晶。ｍｐ＝２３４℃。 Example 82
4-[(5S ^* , 9R ^* )-3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-7-pyrimidin-2-yl-1,3,7-triazaspiro [4.4 ] Nona-9yl] benzonitrile

A mixture of Example 15 (100 mg, 0.24 mmol), K ₂ CO ₃ (37 mg, 0.27 mmol) and 2-bromopyrimidine (42 mg, 0.27 mmol) was heated in DMF (1 mL) at 100 ° C. for 20 hours. did. After cooling to room temperature, the insoluble salt was removed and the filtrate was partitioned between water and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with water and brine, concentrated in vacuo and purified using silica gel chromatography (eluent is 95/5 DCM / MeOH) to give the title compound (36. 1 mg) was obtained. White crystals from MeOH. mp = 234 ° C.

実施例８２と同じ実験方法を用いて、実施例１５（１００ｍｇ、０．２４ｍｍｏｌ）を３,６−ジクロロピリダジン（３９ｍｇ、０．２６ｍｍｏｌ）と反応させて、上記標題化合物（２７．１ｍｇ）（ｍｐ＝１２５℃）を得た。 Example 83
4-[(5S ^* , 9R ^* )-7- (6-chloropyridazin-3-yl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7- Triazaspiro [4.4] non-9-yl] benzonitrile

Using the same experimental method as Example 82, Example 15 (100 mg, 0.24 mmol) was reacted with 3,6-dichloropyridazine (39 mg, 0.26 mmol) to give the title compound (27.1 mg) (mp = 125 ° C).

実施例８２と同じ方法を用いて、実施例１５（１００ｍｇ、０．２４ｍｍｏｌ）を２−ブロモピリジン（２５μＬ、０．２６ｍｍｏｌ）と反応させて、上記標題化合物（３０ｍｇ）を得た。¹H NMR (CDCl₃)：8.22 (1H, m), 7.7 (2H, m), 7.55 (1H, m), 7.39 (2H, m), 7.1 (1H, m), 6.79 (2H, d), 6.70 (1H, m), 6.5 (1H, d), 3.95-4.3 (5H, m), 3.24 (3H, s)。 Example 84
4-[(5S ^* , 9R ^* )-3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-7-pyridin-2-yl-1,3,7-triazaspiro [4.4 ] Nona-9-yl] benzonitrile

Using the same method as Example 82, Example 15 (100 mg, 0.24 mmol) was reacted with 2-bromopyridine (25 μL, 0.26 mmol) to give the title compound (30 mg). ¹ H NMR (CDCl ₃ ): 8.22 (1H, m), 7.7 (2H, m), 7.55 (1H, m), 7.39 (2H, m), 7.1 (1H, m), 6.79 (2H, d), 6.70 (1H, m), 6.5 (1H, d), 3.95-4.3 (5H, m), 3.24 (3H, s).

実施例１５と同じ実験方法を用いて、実施例１１（５３３ｍｇ、１ｍｍｏｌ）をクロロギ酸１−クロロエチルと反応させて、上記標題化合物（７６ｍｇ）（ｍｐ＝１２５℃）を得た。¹H NMR (CDCl₃)：7.66 (2H, d, J = 8.3 Hz), 7.25-7.35 (3H, m), 6.52 (2H, d, J = 1.5 Hz), 4.10 (1H, dd, J₁ = 11.3 Hz, J₂ = 7.1 Hz), 3.74 (1H, d, J = 13.1 Hz), 3.45-3.60 (3H, m), 2.78 (1H, br s), 2.73 (3H, s)。 Example 85
4-[(5S ^* , 9R ^* )-1-acetyl-3- (3,5-dichlorophenyl) -2,4-dioxo-1,3,7-triazaspiro [4.4] non-9-yl] benzo Nitrile

Using the same experimental method as Example 15, Example 11 (533 mg, 1 mmol) was reacted with 1-chloroethyl chloroformate to give the title compound (76 mg) (mp = 125 ° C.). ¹ H NMR (CDCl ₃ ): 7.66 (2H, d, J = 8.3 Hz), 7.25-7.35 (3H, m), 6.52 (2H, d, J = 1.5 Hz), 4.10 (1H, dd, J ₁ = 11.3 Hz, J ₂ = 7.1 Hz), 3.74 (1H, d, J = 13.1 Hz), 3.45-3.60 (3H, m), 2.78 (1H, br s), 2.73 (3H, s).

実施例１５（１００ｍｇ、０．２４ｍｍｏｌ）および無水コハク酸（２４．１ｍｇ、０．２４ｍｍｏｌ）のＤＣＭ（２ｍＬ）溶液を、室温で２４時間撹拌した。乾固するまで濃縮後に、アモルファス固体の上記標題化合物（１２８ｍｇ）を得た。ＬＣマス：保持時間＝１．８７分、Ｍ_ｏｂｓ＝514 (M-1) (LCMS条件：LC Micromass platform (APCI＋, DAD (210-400 nm))、カラム：TSK gel Super ODS 4.6 mm ID × 5 cm、流速：2.75 mL／分、勾配：１００％溶出液Ａ〜１００％溶出液Ｂを２分間、および１００％溶出液Ｂのプラトーを１分間。溶出液ＡはＨ_２Ｏ（０．０５％ＴＦＡ）であり、溶出液ＢはＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡ（８０／２０／０．０５）である。 Example 86
4-[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4. 4] Nona-7-yl] -4-oxo-butyric acid

A solution of Example 15 (100 mg, 0.24 mmol) and succinic anhydride (24.1 mg, 0.24 mmol) in DCM (2 mL) was stirred at room temperature for 24 hours. After concentration to dryness, the title compound (128 mg) was obtained as an amorphous solid. LC mass: retention time = 1.87 minutes, M _obs = 514 (M-1) (LCMS conditions: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 2.75 mL / min, gradient: 100% eluent A to 100% eluent B for 2 minutes, and 100% eluent B plateau for 1 minute, eluent A is H ₂ O (0.05% Eluent B is CH ₃ CN / H ₂ O / TFA (80/20 / 0.05).

実施例８６と同じ実験条件を用いて、実施例１５（１００ｍｇ、０．２４ｍｍｏｌ）をグルタル酸無水物（４１．５ｍｇ、０．３６ｍｍｏｌ）と反応させて、アモルファス固体の上記標題化合物（１３２ｍｇ）を得た。ＬＣマス：保持時間＝１．８９分、Ｍ_ｏｂｓ＝528 (M-1) (LCMS条件：LC Micromass platform (APCI＋, DAD (210-400 nm))、カラム：TSK gel Super ODS 4.6 mm ID × 5 cm、流速：2.75 mL／分、勾配：１００％溶出液Ａ〜１００％溶出液Ｂを２分間、および１００％溶出液Ｂのプラトーを１分間。溶出液ＡはＨ_２Ｏ（０．０５％ＴＦＡ）であり、溶出液ＢはＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡ（８０／２０／０．０５）である。 Example 87
5-[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4. 4] Nona-7-yl] -5-oxo-pentanoic acid

Using the same experimental conditions as Example 86, Example 15 (100 mg, 0.24 mmol) was reacted with glutaric anhydride (41.5 mg, 0.36 mmol) to give the title compound (132 mg) as an amorphous solid. Obtained. LC mass: Retention time = 1.89 min, M _obs = 528 (M-1) (LCMS condition: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 2.75 mL / min, gradient: 100% eluent A to 100% eluent B for 2 minutes, and 100% eluent B plateau for 1 minute, eluent A is H ₂ O (0.05% Eluent B is CH ₃ CN / H ₂ O / TFA (80/20 / 0.05).

シアノ水素化ホウ素ナトリウム（２０２ｍｇ、３．２５ｍｍｏｌ）を、１−エトキシ−１−トリメチルシリルオキシ−シクロプロパン（８７１μＬ、４．３３ｍｍｏｌ）、実施例１５（３００ｍｇ、０．７２ｍｍｏｌ）および酢酸（４１３μＬ、７．２ｍｍｏｌ）のメタノール性溶液（１０ｍＬ）に加えた。該溶液を２．５時間還流し、真空下で濃縮し、そしてＤＣＭおよびブラインの間で分配した。該水相をＤＣＭで２回抽出した。該有機相を合わせてＮａ_２ＳＯ_４を用いて乾燥し、濃縮した。該得られた生成物をＭｅＯＨから結晶化して、白色固体の上記標題化合物（１０７ｍｇ）（ｍｐ＝２１６℃）を得た。 Example 88
4-[(5S ^* , 9R ^* )-7-cyclopropyl-3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] nona 9-yl] benzonitrile

Sodium cyanoborohydride (202 mg, 3.25 mmol) was added to 1-ethoxy-1-trimethylsilyloxy-cyclopropane (871 μL, 4.33 mmol), Example 15 (300 mg, 0.72 mmol) and acetic acid (413 μL, 7. 2 mmol) in methanolic solution (10 mL). The solution was refluxed for 2.5 hours, concentrated under vacuum, and partitioned between DCM and brine. The aqueous phase was extracted twice with DCM. The organic phases were combined, dried using Na ₂ SO ₄ and concentrated. The obtained product was crystallized from MeOH to give the title compound (107 mg) (mp = 216 ° C.) as a white solid.

ホルムアルデヒド（８０μＬ、３７％水溶液、１．１ｍｍｏｌ）を、実施例１５（３００ｍｇ、０．７２ｍｍｏｌ）のギ酸（１ｍＬ）溶液に加えた。９０℃で４時間後に、該溶液を０℃まで冷却し、２Ｎ ＮａＯＨを用いて塩基性とし、そしてＥｔＯＡｃを用いて抽出した。濃縮後に、該化合物をエーテル中でそのＴＦＡ塩を結晶化させることによって精製した。塩基性とした後に、白色固体の上記標題化合物（１２３ｍｇ）を得た。¹H NMR (CDCl₃)：7.63 (2H, d, J = 8.0 Hz), 7.25-7.35 (3H, m), 6.67 (2H, m), 3.83 (1H, dd, J₁ = 11.7 Hz, J₂ = 6.0 Hz), 3.2-3.4 (2H, m), 3.24 (3H, s), 3.09 (1H, m), 2.94 (1H, d, J = 10.9 Hz), 2.52 (3H, s)。 Example 89
4-[(5S ^* , 9R ^* )-3- (3,5-dichlorophenyl) -1,7-dimethyl-2,4-dioxo-1,3,7-triazaspiro [4.4] non-9-yl Benzonitrile

Formaldehyde (80 μL, 37% aqueous solution, 1.1 mmol) was added to a solution of Example 15 (300 mg, 0.72 mmol) in formic acid (1 mL). After 4 hours at 90 ° C., the solution was cooled to 0 ° C., basified with 2N NaOH, and extracted with EtOAc. After concentration, the compound was purified by crystallizing its TFA salt in ether. After basification, the title compound (123 mg) was obtained as a white solid. ¹ H NMR (CDCl ₃ ): 7.63 (2H, d, J = 8.0 Hz), 7.25-7.35 (3H, m), 6.67 (2H, m), 3.83 (1H, dd, J ₁ = 11.7 Hz, J ₂ = 6.0 Hz), 3.2-3.4 (2H, m), 3.24 (3H, s), 3.09 (1H, m), 2.94 (1H, d, J = 10.9 Hz), 2.52 (3H, s).

実施例１６〜２１（方法Ａ）または実施例２２〜２４（方法Ｂ）に記載と同じ方法を用いて、表５に示す上記式（Ｉａｃ）を有する化合物を、ろ過および乾固まで蒸発させた後に、得た。ある化合物は、更に逆相ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡ：５／９５／０．０５〜ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡ：８０／２０／０．０５の勾配を使用）によって精製した。実施例９９および１００は、一般的な方法Ｃ（０．０６ｍｍｏｌのＴＨＦ（３ｍＬ溶液、２Ｎ ＬｉＯＨ（２４０μＬ、０．４８ｍｍｏｌ）溶液を使用）に従って、それらの対応するエステルを加水分解した後に、得た。次いで、これらの化合物を逆相ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡ：５／９５／０．０５〜ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡ：８０／２０／０．０５の勾配を使用）によって精製した。各化合物について、ＬＣマス結果を報告する（LCMS条件：LC Micromass platform (APCI＋, DAD (210-400 nm))、カラム：TSK gel Super ODS 4.6 mm ID × 5 cm、流速：2.75 mL／分、勾配：１００％溶出液Ａ〜１００％溶出液Ｂを２分間、および１００％溶出液Ｂのプラトーを１分間。溶出液ＡはＨ_２Ｏ（０．０５％ＴＦＡ）であり、溶出液ＢはＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡ（８０／２０／０．０５）である。

Examples 90-101

Using the same methods described in Examples 16-21 (Method A) or Examples 22-24 (Method B), the compounds having the above formula (Iac) shown in Table 5 were evaporated to filtration and to dryness. I got it later. Certain compounds are further purified by reverse phase HPLC (using a gradient of CH ₃ CN / H ₂ O / TFA: 5/95 / 0.05 to CH ₃ CN / H ₂ O / TFA: 80/20 / 0.05). Purified. Examples 99 and 100 were obtained after hydrolysis of their corresponding esters according to general method C (using 0.06 mmol of THF (3 mL solution, 2N LiOH (240 μL, 0.48 mmol) solution)). These compounds were then used to reverse phase HPLC (CH ₃ CN / H ₂ O / TFA: 5/95 / 0.05 to CH ₃ CN / H ₂ O / TFA: 80/20 / 0.05 gradient). For each compound, LC mass results are reported (LCMS conditions: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 2.75. mL / min, gradient: 100% eluent A to 100% eluent B for 2 minutes and 100% eluent B plateau for 1 minute, eluent A is H ₂ O (0.05% TFA), eluent B is _CH 3 CN / H It is a O / TFA (80/20 / 0.05).

キノキサリン−６−カルボン酸（５６．２ｍｇ、０．３１８ｍｍｏｌ）のＤＭＦ（７ｍL）溶液に、ＥＤＣＩ（６２ｍｇ、０．３２ｍｍｏｌ）、ＴＦＡ（５３．９μＬ、０．３８ｍｍｏｌ）およびＨＯＢｔ（４９．３ｍｇ、０．３６ｍｍｏｌ）を加えた。３０分後に実施例１５（１０３．４ｍｇ、０．２４９ｍｍｏｌ）のＤＭＦ（１ｍＬ）溶液を加えた。次いで、該反応混合物をＲＴで終夜撹拌し、乾固するまで蒸発させた。該残渣をＤＣＭ（５０ｍＬ）および１Ｎ ＨＣｌ溶液（２０ｍＬ）の間で分配した。該ＤＣＭ相を１０％炭酸水素ナトリウム溶液（２×２０ｍＬ）で洗浄し、硫酸ナトリウムを用いて乾燥し、濃縮し、逆相ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの５／９５／０．０５〜ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの８０／２０／０．０５の勾配を使用）によって精製して、標題化合物（３５ｍｇ）を得た。保持時間は２．１６分。５７１（Ｍ＋１）（LCMS条件：LC Micromass platform (APCI＋, DAD (210-400 nm))、カラム：TSK gel Super ODS 4.6 mm ID × 5 cm、流速：2.75 mL／分、勾配：１００％溶出液Ａ〜１００％溶出液Ｂを２分間、および１００％溶出液Ｂのプラトーを１分間。溶出液ＡはＨ_２Ｏ（０．０５％ＴＦＡ）であり、溶出液ＢはＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡ（８０／２０／０．０５）である。 Example 102
4-[(5S ^* , 9R ^* )-3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-7- (quinoxaline-6-carbonyl) -1,3,7-triazaspiro [4 .4] Nona-9-yl] benzonitrile

To a solution of quinoxaline-6-carboxylic acid (56.2 mg, 0.318 mmol) in DMF (7 mL), EDCI (62 mg, 0.32 mmol), TFA (53.9 μL, 0.38 mmol) and HOBt (49.3 mg, 0 .36 mmol) was added. After 30 minutes, a solution of Example 15 (103.4 mg, 0.249 mmol) in DMF (1 mL) was added. The reaction mixture was then stirred at RT overnight and evaporated to dryness. The residue was partitioned between DCM (50 mL) and 1N HCl solution (20 mL). The DCM phase was washed with 10% sodium bicarbonate solution (2 × 20 mL), dried with sodium sulfate, concentrated and reverse phase HPLC (CH ₃ CN / H ₂ O / TFA 5/95/0. Purification using a gradient of 05 / CH ₃ CN / H ₂ O / TFA 80/20 / 0.05) afforded the title compound (35 mg). Retention time is 2.16 minutes. 571 (M + 1) (LCMS conditions: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 2.75 mL / min, gradient: 100% eluent A 100% eluent B for 2 minutes, and 100% for 1 min. eluent a plateau of eluent B is _{H 2 O (0.05% TFA)} , eluent B is _CH 3 CN _{/ H} 2 O / TFA (80/20 / 0.05).

実施例２５〜３６に記載と同じ方法（方法Ｄ）を用いて、表６に示す上記式（Ｉａｅ）を有する化合物を、ろ過および乾固するまで蒸発させた後に、得た。Ｎ−Ｂｏｃおよび／またはＣＯ_２ｔＢｕ保護のＲについては、該化合物をＤＣＭ／ＴＦＡ（１：１）溶液を用いてＲＴで２時間処理し、そして得られた塩基性または酸性の化合物を更に、それぞれＳＣＸまたはＳＡＸカートリッジによって精製した（方法Ｌ）。 Examples 103-104

Using the same method as described in Examples 25-36 (Method D), the compounds having the above formula (Iae) shown in Table 6 were obtained after filtration and evaporation to dryness. For N-Boc and / or CO ₂ tBu protected R, the compound is treated with DCM / TFA (1: 1) solution for 2 hours at RT and the resulting basic or acidic compound is further treated with Purified by SCX or SAX cartridge, respectively (Method L).

Furthermore certain compounds by reverse phase HPLC _(using a gradient of _{CH 3 CN / H 2 O /} TFA for _{5/95 / 0.05~CH 3 CN /} H 2 of O / TFA 80/20 / 0.05 ) Purified. LC mass results are reported for each compound (LCMS conditions: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 2.75 mL / min, gradient : 100% eluent A to 100% eluent B for 2 minutes and 100% eluent B plateau for 1 minute, eluent A is H ₂ O (0.05% TFA), eluent B is CH ₃ CN / H ₂ O / TFA (80/20 / 0.05).

ジカルボン酸試薬（０．２４ｍｍｏｌ）に、１ｍＬのＥＤＣＩ（９５．９ｍｇ、０．５ｍｍｏｌ）およびＴＥＡ（８４μＬ、０．６ｍｍｏｌ）混合物のＤＭＦ（７ｍＬ）、および０．１ｍＬのＨＯＢｔ（７８ｍｇ、０．５７ｍｍｏｌのＤＭＦ（０．７ｍＬ）溶液を加えた。１５分後に、０．３ｍＬの実施例１５溶液（１７４．５ｍｇ、０．４２ｍｍｏｌ、ＤＭＦ（２．１ｍＬ）中）を加えた。次いで、該反応混合物をＲＴで終夜撹拌し、そして乾固するまで蒸発させた（方法Ｅ）。該残渣を逆相ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの５／９５／０．０５〜ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの８０／２０／０．０５の勾配を使用）によって精製して、表７に示す上記式（Ｉａｅ）を有する化合物を得た。ＬＣマス結果を報告する（LCMS条件：LC Micromass platform (APCI＋, DAD (210-400 nm))、カラム：TSK gel Super ODS 4.6 mm ID × 5 cm、流速：2.75 mL／分、勾配：１００％溶出液Ａ〜１００％溶出液Ｂを２分間、および１００％溶出液Ｂのプラトーを１分間。溶出液ＡはＨ_２Ｏ（０．０５％ＴＦＡ）であり、溶出液ＢはＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡ（８０／２０／０．０５）である。

Examples 135-140

To the dicarboxylic acid reagent (0.24 mmol) was added 1 mL of EDCI (95.9 mg, 0.5 mmol) and TEA (84 μL, 0.6 mmol) in DMF (7 mL), and 0.1 mL of HOBt (78 mg, 0.57 mmol). Of DMF (0.7 mL) was added 15 min later, 0.3 mL of Example 15 solution (174.5 mg, 0.42 mmol, in DMF (2.1 mL)) was added. was stirred overnight at RT, and evaporated to dryness (method E). the residue of the reverse phase _{HPLC (CH 3 CN / H 2} O / TFA 5/95 / 0.05~CH 3 CN / H ₂ O / use 80/20 / 0.05 gradient of TFA) to give the report .LC mass results give the compound having the formula shown in Table 7 (Iae) (LCMS conditions LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID x 5 cm, flow rate: 2.75 mL / min, gradient: 100% eluent A to 100% eluent B Minutes and a plateau of 100% eluent B. Eluent A is H ₂ O (0.05% TFA) and eluent B is CH ₃ CN / H ₂ O / TFA (80/20/0 .05).

無水カルボン酸試薬（０．０７２ｍｍｏｌ）のＴＨＦ（１．５ｍＬ）溶液に、０．５ｍＬの実施例１５（４４８．５ｍｇ、１．０８ｍｍｏｌ、ＴＨＦ（９ｍＬ）中）溶液を加えた。該反応混合物をＲＴで終夜撹拌し、乾固するまで蒸発させた（方法Ｆ）。次いで、該化合物をＳＡＸカートリッジによって精製して、そしてあるものは更に、逆相（ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの５／９５／０．０５〜ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの８０／２０／０．０５の勾配を使用）によって精製して、表８に示す上記式（Ｉａｇ）を有する化合物を得た。ＬＣマス結果を報告する（LCMS:条件：LC Micromass platform (APCI＋, DAD (210-400 nm))、カラム：TSK gel Super ODS 4.6 mm ID × 5 cm、流速：2.75 mL／分、勾配：１００％溶出液Ａ〜１００％溶出液Ｂを２分間、および１００％溶出液Ｂのプラトーを１分間。溶出液ＡはＨ_２Ｏ（０．０５％ＴＦＡ）であり、溶出液ＢはＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡ（８０／２０／０．０５）である。

Examples 141-151

To a solution of carboxylic anhydride reagent (0.072 mmol) in THF (1.5 mL) was added 0.5 mL of Example 15 (448.5 mg, 1.08 mmol, in THF (9 mL)) solution. The reaction mixture was stirred at RT overnight and evaporated to dryness (Method F). The compounds were then purified by SAX cartridges, and some were further reversed phase (CH ₃ CN / H ₂ O / TFA 5/95 / 0.05 to CH ₃ CN / H ₂ O / TFA 80 The compound having the above formula (Iag) shown in Table 8 was obtained. LC mass results are reported (LCMS: conditions: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 2.75 mL / min, gradient: 100% Eluent A-100% Eluent B for 2 minutes and 100% Eluent B plateau for 1 minute Eluent A is H ₂ O (0.05% TFA) and Eluent B is CH ₃ CN / a _{H 2 O / TFA (80/} 20 / 0.05).

実施例１５（４１．５ｍｇ、０．１ｍｍｏｌ）のＴＨＦ（１ｍＬ）溶液に、ＴＥＡ（０．０１９４ｍＬ、０．１４ｍｍｏｌ）およびクロロアセチルクロリド（０．００９５ｍＬ、０．１２ｍｍｏｌ）を加えた。ＲＴで１５分後に、該反応混合物を乾固するまで蒸発させて、粗中間体（４７．８ｍｇ）を得た。この中間体（３７．７ｍｇ、０．０７７ｍｍｏｌ）のＴＨＦ（１ｍＬ）に、ＰＳ−ＤＩＥＡ（Argonaut、２１ｍｇ、０．０６ｍｍｏｌ）、ベンジルアミン（４．９μＬ、０．０４５ｍｍｏｌ）およびＰＳ−ＤＭＡＰ（Argonaut、２０ｍｇ、０．０６ｍｍｏｌ）を加えた。該反応混合物をＲＴで２４時間撹拌し、乾固するまで蒸発させた。該残渣を逆相ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの５／９５／０．０５〜ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの８０／２０／０．０５の勾配を使用）によって精製して、標題化合物（４．２ｍｇ）を得た。保持時間：１０．６５分。５６３（Ｍ＋１）；（LCMS条件：HP 1100 MSD platform (APCI−, DAD (210-400 nm))、カラム：TSK gel Super ODS 4.6 mm ID × 5 cm、流速：1 mL／分、勾配：５％〜９５％溶出液Ｂを１５分間、および９５％溶出液Ｂのプラトーを５分間。溶出液ＡはＨ_２Ｏ（０．１％ギ酸アンモニウム）であり、溶出液ＢはＣＨ_３ＣＮである。¹H NMR (CDCl₃)：7.75-7.6 (2H, d), 7.6-7.15 (8H, m), 7.75 (2H, d), 4.25 (2H, s), 4.2-3.6 (7H,m), 3.3-3.05 (3H, m)。 Example 152
4-[(5S ^* , 9R ^* )-7- (2-benzylamino-acetyl) -3- (3,5-dichloro-phenyl) -1-methyl-2,4-dioxo-1,3,7- Triazaspiro [4.4] non-9-yl] benzonitrile

To a solution of Example 15 (41.5 mg, 0.1 mmol) in THF (1 mL) was added TEA (0.0194 mL, 0.14 mmol) and chloroacetyl chloride (0.0095 mL, 0.12 mmol). After 15 minutes at RT, the reaction mixture was evaporated to dryness to give the crude intermediate (47.8 mg). To this intermediate (37.7 mg, 0.077 mmol) in THF (1 mL) was added PS-DIEA (Argonaut, 21 mg, 0.06 mmol), benzylamine (4.9 μL, 0.045 mmol) and PS-DMAP (Argonaut, 20 mg, 0.06 mmol) was added. The reaction mixture was stirred at RT for 24 hours and evaporated to dryness. The residue was purified by reverse phase HPLC _(CH 3 using a gradient of _CN / H 2 O / TFA for _{5/95 / 0.05~CH 3 CN /} H 2 O / TFA 80/20 / 0.05) To give the title compound (4.2 mg). Retention time: 10.65 minutes. 563 (M + 1); (LCMS conditions: HP 1100 MSD platform (APCI-, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 1 mL / min, gradient: 5% ˜95% eluent B for 15 minutes and 95% eluent B plateau for 5 minutes, eluent A is H ₂ O (0.1% ammonium formate) and eluent B is CH ₃ CN. ¹ H NMR (CDCl ₃ ): 7.75-7.6 (2H, d), 7.6-7.15 (8H, m), 7.75 (2H, d), 4.25 (2H, s), 4.2-3.6 (7H, m), 3.3 -3.05 (3H, m).

表９に示す上記式（Ｉａｈ）を有する化合物は、実施例１５（１０．９ｍｇ、０．０４５ｍｍｏｌ）およびＴＥＡ（６．７４μＬ、０．０４８ｍｍｏｌ）を適当なアルキル、アリールまたはヘテロアリールのブロミド試薬（ＲＲ^'ＣＨＢｒ）（０．０３ｍｍｏｌ）のジオキサン（１ｍＬ）溶液に加えることによって、得た。該反応混合物をＲＴで終夜撹拌し、乾固するまで蒸発させた（方法Ｇ）。該化合物をＳＣＸカートリッジおよびＰＳ−イソシアネート（Argonaut、０．０６ｍｍｏｌ）によって精製した；ある化合物はまた、逆相ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの５／９５／０．０５〜ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの８０／２０／０．０５の勾配を使用）によって精製した。実施例１６２〜１６４は、実施例９０〜１０１と同様に一般的な方法Ｃに従って、それらの対応するエステを加水分解させた後に、得た。次いで、これらの化合物は、逆相ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの５／９５／０．０５〜ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの８０／２０／０．０５の勾配を使用）によって精製した。ＬＣマス結果を報告する（LCMS条件：LC Micromass platform (APCI＋, DAD (210-400 nm))、カラム：TSK gel Super ODS 4.6 mm ID × 5 cm、流速：2.75 mL／分、勾配：１００％溶出液Ａ〜１００％溶出液Ｂを２分間、および１００％溶出液Ｂのプラトーを１分間。溶出液ＡはＨ_２Ｏ（０．０５％ＴＦＡ）であり、溶出液ＢはＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡ（８０／２０／０．０５）である。

Examples 153-162

The compounds having the above formula (Iah) shown in Table 9 were prepared by converting Example 15 (10.9 mg, 0.045 mmol) and TEA (6.74 μL, 0.048 mmol) into appropriate alkyl, aryl or heteroaryl bromide reagents ( by adding in dioxane (1 mL) solution of RR ^'CHBr) (0.03mmol), it was obtained. The reaction mixture was stirred at RT overnight and evaporated to dryness (Method G). The compound was purified by SCX cartridge and PS-isocyanate (Argonaut, 0.06 mmol); some compounds were also reverse phase HPLC (CH ₃ CN / H ₂ O / TFA 5/95 / 0.05 to CH ₃ CN / H ₂ O / TFA 80/20 / 0.05 gradient). Examples 162-164 were obtained after hydrolyzing their corresponding esthetics according to General Method C as in Examples 90-101. Then, these compounds, using a gradient reverse phase _{HPLC (CH 3 CN / H 2} O / TFA for _{5/95 / 0.05~CH 3 CN /} H 2 O / TFA 80/20 / 0.05 ). LC mass results are reported (LCMS conditions: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 2.75 mL / min, gradient: 100% elution Solution A to 100% Eluent B for 2 minutes, and plateau of 100% Eluent B for 1 minute, Eluent A is H ₂ O (0.05% TFA), Eluent B is CH ₃ CN / H ₂ O / TFA (80/20 / 0.05).

実施例１５（８７３．１ｍｇ、２．１ｍｍｏｌ）およびＴＥＡ（４０８μＬ、２．９４ｍｍｏｌ）のＴＨＦ（５ｍＬ）溶液に、１,１'−カルボニルジイミダゾール（４７９．３ｍｇ、２．９４ｍｍｏｌ、ＴＨＦ（６ｍＬ）中）溶液を滴下した。該反応混合物をＲＴで２４時間撹拌し、乾固するまで蒸発させた。該残渣をＤＣＭ（５０ｍＬ）およびブライン（２０ｍＬ）の間で分配した。該ＤＣＭ相を硫酸ナトリウムを用いて乾燥し、そして濃縮した。この残渣をヨウ化メチル（５２３μＬ、８．４ｍｍｏｌ）と一緒にＡＣＮ（２０ｍＬ）中、６０℃で終夜撹拌し、そして該反応混合物を乾固するまで蒸発させ、該粗反応性中間体を得た。 Examples 163 to 181

To a solution of Example 15 (873.1 mg, 2.1 mmol) and TEA (408 μL, 2.94 mmol) in THF (5 mL) was added 1,1′-carbonyldiimidazole (479.3 mg, 2.94 mmol, THF (6 mL). Medium) The solution was added dropwise. The reaction mixture was stirred at RT for 24 hours and evaporated to dryness. The residue was partitioned between DCM (50 mL) and brine (20 mL). The DCM phase was dried using sodium sulfate and concentrated. The residue was stirred with methyl iodide (523 μL, 8.4 mmol) in ACN (20 mL) at 60 ° C. overnight and the reaction mixture was evaporated to dryness to give the crude reactive intermediate. .

To a solution of appropriately substituted amine or alcohol reagent (RXH) (0.072 mmol) in DCM / DMF (8/2) (1.8 mL) with 0.5 mL of TEA (0.5 mL, 3.56 mmol). A solution of the reactive intermediate (1.62 mmol) in DCM (13 mL) was added. The reaction mixture was stirred at RT overnight and evaporated to dryness (Method H). The compound was purified by reverse phase HPLC _(CH 3 using a gradient of _CN / H 2 O / TFA for _{5/95 / 0.05~CH 3 CN /} H 2 O / TFA 80/20 / 0.05) Thus, compounds having the above formula (Iai) shown in Table 10 were obtained. Examples 174-179 were obtained after hydrolysis of their corresponding esters according to general method C as in Examples 90-101. Then, _(using 80/20 / 0.05 gradient of _{5/95 / 0.05~CH 3 CN /} H 2 O / TFA in _{CH 3 CN / H 2 O /} TFA) of these compounds by reverse phase HPLC Purified by LC mass results are reported (LCMS conditions: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 2.75 mL / min, gradient: 100% elution Solution A to 100% Eluent B for 2 minutes, and plateau of 100% Eluent B for 1 minute, Eluent A is H ₂ O (0.05% TFA), Eluent B is CH ₃ CN / H ₂ O / TFA (80/20 / 0.05).

実施例１５（２４．９ｍｇ、０．０６ｍｍｏｌ）のＴＨＦ／ＤＭＦ（９／１）（１ｍＬ）溶液に、イソシアネート酢酸エチル（１１．６ｍｇ、０．０８９ｍｍｏｌ）を加え、そして該反応混合物をＲＴで終夜撹拌した。該標題化合物（３３．３ｍｇ）を、ＰＳ−トリサミン（Argonaut、７３ｍｇ、０．２６７ｍｍｏｌ）およびＰＳ−イソシアネート（Argonaut、８５ｍｇ、０．１２２ｍｍｏｌ）を用いて処理後に、得た。保持時間：１．９９分、５４４（Ｍ＋１）；（LCMS条件：LC Micromass platform (APCI＋, DAD (210-400 nm))、カラム：TSK gel Super ODS 4.6 mm ID × 5 cm、流速：2.75 mL／分、勾配：１００％溶出液Ａ〜１００％溶出液Ｂを２分間、および１００％溶出液Ｂのプラトーを１分間。溶出液ＡはＨ_２Ｏ（０．０５％ＴＦＡ）であり、溶出液ＢはＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡ（８０／２０／０．０５）である。 Example 182
{[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4 ] Nonane-7-carbonyl] amino} acetic acid ethyl ester

To a solution of Example 15 (24.9 mg, 0.06 mmol) in THF / DMF (9/1) (1 mL) was added ethyl isocyanate isocyanate (11.6 mg, 0.089 mmol) and the reaction mixture was stirred overnight at RT. Stir. The title compound (33.3 mg) was obtained after treatment with PS-trisamine (Argonaut, 73 mg, 0.267 mmol) and PS-isocyanate (Argonaut, 85 mg, 0.122 mmol). Retention time: 1.99 minutes, 544 (M + 1); (LCMS conditions: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 2.75 mL / Min, gradient: 100% eluent A to 100% eluent B for 2 minutes and 100% eluent B plateau for 1 minute, eluent A is H ₂ O (0.05% TFA), eluent B is CH ₃ CN / H ₂ O / TFA (80/20 / 0.05).

表１１に示す上記式（Ｉａｊ）を有する化合物を、以下の方法Ｉまたは方法Ｊのいずれかによって、ＳＣＸカートリッジ精製後に、得た。ある化合物は更に、逆相ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの５／９５／０．０５〜ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの８０／２０／０．０５の勾配を使用）によって精製した。実施例２０７は、実施例９０〜１０１と同様に一般的な方法Ｃに従ってその対応するエチルエステルを加水分解させた後に、得て、そして逆相ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの５／９５／０．０５〜ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの８０／２０／０．０５の勾配を使用）によって得た。 Examples 183 to 216

The compounds having the above formula (Iaj) shown in Table 11 were obtained after SCX cartridge purification by either method I or method J below. Furthermore certain compounds by reverse phase HPLC _(using a gradient of _{CH 3 CN / H 2 O /} TFA for _{5/95 / 0.05~CH 3 CN /} H 2 of O / TFA 80/20 / 0.05 ) Purified. Example 207 was obtained after hydrolysis of its corresponding ethyl ester according to general method C as in Examples 90-101 and reverse phase HPLC (CH ₃ CN / H ₂ O / TFA 5 /95/0.05 to CH ₃ CN / H ₂ O / TFA 80/20 / 0.05 gradient).

  Method I: To a solution of aldehyde reagent (0.12 mmol) in 1,2-DCE (1.2 mL), sodium sulfate (12.8 mg) and 0.5 mL of Example 15 solution (0.797 mg, 1.92 mmol, 1 , 2-DCE (in 16 mL)) was added. The reaction mixture was then stirred at RT for 24 hours and sodium triacetoxyborohydride (20 mg, 0.084 mmol) was added. The reaction was continued for 24 hours at RT.

Method J: To a solution of aldehyde reagent (0.135 mmol) and sodium triacetoxyborohydride (19 mg, 0.09 mmol) in 1,2-DCE (1.5 mL) was added 0.04 mL of trimethyl orthoformate / acetic acid (10. 5 mL / 0.225 mL) mixture and 0.5 mL of Example 15 solution (0.486 mg, 1.17 mmol, in 1,2-DCE (75 mL)) were added. The reaction mixture was then stirred at RT for 24 hours and treated with PS-TsNHNH ₂ (Argonaut, 159 mg, 0.405 mmol).

For each compound, the LC mass results are reported in Table 11 (LCMS conditions: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 2.75 mL / Min, gradient: 100% eluent A to 100% eluent B for 2 minutes and 100% eluent B plateau for 1 minute, eluent A is H ₂ O (0.05% TFA), eluent B is CH ₃ CN / H ₂ O / TFA (80/20 / 0.05).

ＰＳ−カルボジイミド（Argonaut、０．９６ｍｍｏｌ／ｇ、７４ｍｇ、０．０７１ｍｍｏｌ）のヒドロキシアザベンゾトリアゾール溶液（１５３ｍＭ ＤＣＭ｛２５％ＤＭＦ｝、０．０５ｍｍｏｌ）（０．３３ｍＬ）懸濁液に、０．５ｍＬの実施例６４（６０ｍＭ ＤＣＭ｛２０％ＤＭＦ｝、０．０３ｍｍｏｌ）溶液、および０．５ｍＬの目的のアミン試薬ＲＲ^’ＮＨ（５４ｍＭ ＤＣＭ｛２０％ ＤＭＦ｝、０．０２７ｍｍｏｌ）を有する溶液を加えた。ＲＴで２４時間後に、該混合物をＰＳ−トリサミン（Argonaut、３．６５ｍｍｏｌ／ｇ、６５ｍｇ、０．２４ｍｍｏｌ）を用いて終夜処理した。該ろ過した溶液を乾固するまで蒸発させた後に、表１２に示す式（Ｉａｋ）を有する化合物を得た。Ｎ−Ｂｏｃおよび／またはＣＯ_２ｔＢｕ保護の酸の場合には（実施例２４５〜２５０）、該化合物をＤＣＭ／ＴＦＡ（１：１）溶液を用いてＲｔで２時間処理し、その後にそれぞれＳＣＸまたはＳＡＸカートリッジ精製を行った（方法Ｌ）。実施例２４２〜２４４は、実施例９０〜１０１と同様に一般的な方法Ｃに従ってそれらの対応するエステルを加水分解させた後に、得た。次いで、これらの化合物をＳＡＸカートリッジによって精製した。ある化合物は、逆相ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの５／９５／０．０５〜ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの８０／２０／０．０５の勾配を使用）によって精製後に、得た。 Examples 217-250

To a suspension of PS-carbodiimide (Argonaut, 0.96 mmol / g, 74 mg, 0.071 mmol) in hydroxyazabenzotriazole (153 mM DCM {25% DMF}, 0.05 mmol) (0.33 mL), 0.5 mL example 64 (60mM DCM {20% DMF }, 0.03mmol) solution, and an object of the amine reagent RR ^'NH of 0.5mL (54mM DCM {20% DMF }, 0.027mmol) was added a solution with . After 24 hours at RT, the mixture was treated with PS-trisamine (Argonaut, 3.65 mmol / g, 65 mg, 0.24 mmol) overnight. After evaporating the filtered solution to dryness, the compounds having the formula (Iak) shown in Table 12 were obtained. In the case of N-Boc and / or CO ₂ tBu protected acid (Examples 245-250), the compound was treated with DCM / TFA (1: 1) solution for 2 hours at Rt, followed by SCX Alternatively, SAX cartridge purification was performed (Method L). Examples 242 to 244 were obtained after hydrolysis of their corresponding esters according to General Method C as in Examples 90 to 101. These compounds were then purified by SAX cartridges. Certain compounds purified by reverse-phase HPLC _(CH 3 using a gradient of _CN / H 2 O / TFA for _{5/95 / 0.05~CH 3 CN /} H 2 O / TFA 80/20 / 0.05) I got it later.

The LC mass results for each compound are reported in Table 12 (LCMS conditions: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 2.75 mL / Min, gradient: 100% eluent A to 100% eluent B for 2 minutes and 100% eluent B plateau for 1 minute, eluent A is H ₂ O (0.05% TFA), eluent B is CH ₃ CN / H ₂ O / TFA (80/20 / 0.05).

表１３に示す式（Ｉａｊ）を有する化合物は、実施例１５４〜１６２および１８３〜２１６に記載する方法ＧまたはＩを用い、ＳＣＸカートリッジ精製後に、得た。ある化合物は更に、逆相ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの５／９５／０．０５〜ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの８０／２０／０．０５の勾配を使用）によって精製した。実施例２６８は、実施例９０〜１０１と同様に一般的な方法Ｃに従って、その対応するエチルエステル（実施例２６７）を加水分解させた後に、得た。各化合物について、ＬＣマス結果を表１３に報告する（LCMS条件：LC Micromass platform (APCI＋, DAD (210-400 nm))、カラム：TSK gel Super ODS 4.6 mm ID × 5 cm、流速：2.75 mL／分、勾配：１００％溶出液Ａ〜１００％溶出液Ｂを２分間、および１００％溶出液Ｂのプラトーを１分間。溶出液ＡはＨ_２Ｏ（０．０５％ＴＦＡ）であり、溶出液ＢはＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡ（８０／２０／０．０５）である。

Examples 251 to 268

Compounds having formula (Iaj) shown in Table 13 were obtained after SCX cartridge purification using Method G or I described in Examples 154-162 and 183-216. Furthermore certain compounds by reverse phase HPLC _(using a gradient of _{CH 3 CN / H 2 O /} TFA for _{5/95 / 0.05~CH 3 CN /} H 2 of O / TFA 80/20 / 0.05 ) Purified. Example 268 was obtained after hydrolysis of its corresponding ethyl ester (Example 267) according to General Method C as in Examples 90-101. For each compound, LC mass results are reported in Table 13 (LCMS conditions: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 2.75 mL / Min, gradient: 100% eluent A to 100% eluent B for 2 minutes and 100% eluent B plateau for 1 minute, eluent A is H ₂ O (0.05% TFA), eluent B is CH ₃ CN / H ₂ O / TFA (80/20 / 0.05).

表１４に示す上記式（Ｉａｌ）を有する化合物は、０．１ｍＬのＴＥＡ溶液（７２０ｍＭのＴＨＦ溶液、０．０７２ｍｍｏｌ）、０．１ｍＬのＤＭＡＰ溶液（６０ｍＭのＴＨＦ溶液、０．００６ｍｍｏｌ）、および１ｍＬの製造例２５溶液（６０ｍＭのＴＨＦ溶液、０．０６ｍｍｏｌ）を、適当に置換したアミンＲＲ^’ＮＨ溶液（０．５ｍＬ、１８ｍＭのＴＨＦ溶液、０．０９ｍｍｏｌ）に加えた。該反応混合物をＲＴで終夜撹拌し、そして乾固するまで蒸発させた（方法Ｍ）。該残渣を逆相ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの５／９５／０．０５〜ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの８０／２０／０．０５の勾配を使用）によって精製した。Ｎ−Ｂｏｃおよび／またはＣＯ_２ｔＢｕの保護化合物は、ＤＣＭ／ＴＦＡ（１：１）溶液を用いてＲＴで２時間処理し、続いて得られた塩基性または酸性の化合物についてそれぞれＳＣＸまたはＳＡＸカートリッジ精製を行なった（方法Ｌ）。ＬＣマス結果を報告する（APCI＋, DAD (210-400 nm))、カラム：TSK gel Super ODS 4.6 mm ID × 5 cm、流速：2.75 mL／分、勾配：１００％溶出液Ａ〜１００％溶出液Ｂを２分間、および１００％溶出液Ｂのプラトーを１分間。溶出液ＡはＨ_２Ｏ（０．０５％ＴＦＡ）であり、溶出液ＢはＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡ（８０／２０／０．０５）である。

Examples 269-278

The compounds having the above formula (Ial) shown in Table 14 are 0.1 mL TEA solution (720 mM THF solution, 0.072 mmol), 0.1 mL DMAP solution (60 mM THF solution, 0.006 mmol), and 1 mL. examples of preparation 25 solution (THF solution of 60 mM, 0.06 mmol) and an appropriately substituted amine RR ^'NH solution (0.5 mL, THF solution of 18 mM, 0.09 mmol) was added to. The reaction mixture was stirred at RT overnight and evaporated to dryness (Method M). The residue was purified by reverse phase HPLC _(CH 3 using a gradient of _CN / H 2 O / TFA for _{5/95 / 0.05~CH 3 CN /} H 2 O / TFA 80/20 / 0.05) . N-Boc and / or CO ₂ tBu protected compounds were treated with DCM / TFA (1: 1) solution for 2 hours at RT, followed by SCX or SAX cartridge for the resulting basic or acidic compounds, respectively. Purification was performed (Method L). Report LC mass results (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID x 5 cm, flow rate: 2.75 mL / min, gradient: 100% eluent A to 100% eluent B for 2 minutes and 100% eluent B plateau for 1 minute. The eluent A is H ₂ O (0.05% TFA), and the eluent B is CH ₃ CN / H ₂ O / TFA (80/20 / 0.05).

実施例１１に記載する実験方法を用いて、製造例２０（５．６ｇ、１５ｍｍｏｌ）を、白色固体の上記標題化合物（７．５ｇ）（ｍｐ＝１７４〜１７６℃）に変換した。¹H NMR (CDCl₃)：7.60 (2H, d, J = 8 Hz), 7.25-7.35 (7H, m), 7.11 (2H, m), 3.65-4.0 (4H, m), 3.0-3.4 (2H, m), 3.23 (3H, s), 2.97 (1H, d, J = 10.9 Hz)。 Example 279
4-[(5S ^* , 9R ^* )-7-benzyl-3- (2,6-dichloro-pyridin-4-yl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4 .4] Nona-9-yl] benzonitrile

Using the experimental method described in Example 11, Preparation 20 (5.6 g, 15 mmol) was converted to the title compound (7.5 g) (mp = 174-176 ° C.) as a white solid. ¹ H NMR (CDCl ₃ ): 7.60 (2H, d, J = 8 Hz), 7.25-7.35 (7H, m), 7.11 (2H, m), 3.65-4.0 (4H, m), 3.0-3.4 (2H m), 3.23 (3H, s), 2.97 (1H, d, J = 10.9 Hz).

トリフルオロ酢酸（１２２μＬ、１．６ｍｍｏｌ）を、ＤＣＭ（３ｍＬ）中、製造例２７（９７ｍｇ、０．１６ｍｍｏｌ）の冷（５℃）溶液に加えた。ＲＴで２４時間後に、水を加え、そしてｐＨをＮＨ_４ＯＨを用いて１０とした。次いで、ＳＯ_２をその溶液中にバブルしてｐＨ＝６とした。該有機層を分離した。該水相をＤＣＭを用いて２回抽出した。該有機層を合わせてＭｇＳＯ_４を用いて乾燥し、そして真空下で濃縮した。得られた化合物を、アセトニトリルを加えることによって結晶化させた。該固体をエーテルおよびペンタンで洗浄して、オフホワイト色固体の上記標題化合物（７．５ｍｇ）を得た。保持時間は８．１分である。５３３（Ｍ−１）；LCMS条件：HP 1100 MSD platform（APCI−, DAD (210-400 nm))、カラム：TSK gel Super ODS 4.6 mm ID × 5 cm、流速：１ｍＬ／分、勾配：５％〜９５％溶出液Ｂを１５分間、および９５％溶出液Ｂのプラトーを５分間。溶出液ＡはＨ_２Ｏ（０．１％ギ酸アンモニウム）であり、溶出液ＢはＣＨ_３ＣＮである。 Example 280
4-[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4. 4] Nona-9-yl] benzoic acid

Trifluoroacetic acid (122 μL, 1.6 mmol) was added to a cold (5 ° C.) solution of Preparation 27 (97 mg, 0.16 mmol) in DCM (3 mL). After 24 hours at RT, water was added and the pH was brought to 10 with NH ₄ OH. SO ₂ was then bubbled into the solution to pH = 6. The organic layer was separated. The aqueous phase was extracted twice with DCM. The organic layers were combined, dried using MgSO ₄ and concentrated in vacuo. The resulting compound was crystallized by adding acetonitrile. The solid was washed with ether and pentane to give the title compound (7.5 mg) as an off-white solid. The retention time is 8.1 minutes. 533 (M-1); LCMS conditions: HP 1100 MSD platform (APCI-, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 1 mL / min, gradient: 5% -95% eluent B for 15 minutes and 95% eluent B plateau for 5 minutes. Eluent A is H ₂ O (0.1% ammonium formate), and eluent B is CH ₃ CN.

実施例１０２と同じ方法を用いて、上記標題化合物を、実施例１５（４１．３ｍｇ、０．１ｍｍｏｌ）およびテトラゾール−５−酢酸（２２ｍｇ、０．１７ｍｍｏｌ）から逆相ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの５／９５／０．０５〜ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの８０／２０／０．０５の勾配を使用）による精製後に、得た。¹H NMR (CDCl₃)：7.65-7.5 (2H, m), 7.35-7.1 (3H, m), 6.67 (2H, d), 4.5-3.7 (7H, m), 3.1 (3H, d)。 Example 281
4-[(5S ^* , 9R ^* )-3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-7- (2-1H-tetrazol-5-yl-acetyl) -1,3 , 7-Triazaspiro [4.4] non-9-yl] benzonitrile

Using the same method as Example 102, the title compound was obtained from Example 15 (41.3 mg, 0.1 mmol) and tetrazole-5-acetic acid (22 mg, 0.17 mmol) using reverse phase HPLC (CH ₃ CN / H after purification by using _5/95 / gradient of _{0.05~CH 3 CN / H 2 O /} TFA 80/20 / 0.05 ₂ O / TFA), were obtained. ¹ H NMR (CDCl ₃ ): 7.65-7.5 (2H, m), 7.35-7.1 (3H, m), 6.67 (2H, d), 4.5-3.7 (7H, m), 3.1 (3H, d).

実施例１５（２４．９ｍｇ、０．０６ｍｍｏｌ）のＣＨ_３ＣＮ（１ｍＬ）に、ヨウ化ナトリウム（８，４ｍｇ、０．０８４ｍｍｏｌ）、炭酸カリウム（５．５ｍｇ、０．０６ｍｍｏｌ）および５−(２−クロロエチル)−１Ｈ−テトラゾール（５．３ｍｇ、０．０４ｍｍｏｌ）を加えた。該反応混合物を７０℃で終夜撹拌した。該上記標題化合物（１．３ｍｇ）は、ＳＣＸカートリッジ精製およびＰＳ−イソシアネート処理（Argonaut、８３ｍｇ）後に、得た。保持時間は１．３６分である、Ｍ_ｏｂｓ＝511 (M＋1)（LCMS条件：LC Micromass platform (APCI＋, DAD (210-400 nm))、カラム：TSK gel Super ODS 4.6 mm ID × 5 cm、流速：2.75 mL／分、勾配：１００％溶出液Ａ〜１００％溶出液Ｂを２分間、および１００％溶出液Ｂのプラトーを１分間。溶出液ＡはＨ_２Ｏ（０．０５％ＴＦＡ）であり、溶出液ＢはＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡ（８０／２０／０．０５）である。 Example 282
4-{(5S ^* , 9R ^* )-3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-7- [2- (1H-tetrazol-5-yl) ethyl] -1, 3,7-triazaspiro [4.4] non-9-yl} benzonitrile

Example 15 (24.9 mg, 0.06 mmol) in _CH 3 CN (1 mL), and sodium iodide (8,4mg, 0.084mmol), potassium carbonate (5.5 mg, 0.06 mmol) and 5- (2 -Chloroethyl) -1H-tetrazole (5.3 mg, 0.04 mmol) was added. The reaction mixture was stirred at 70 ° C. overnight. The title compound (1.3 mg) was obtained after SCX cartridge purification and PS-isocyanate treatment (Argonaut, 83 mg). Retention time is 1.36 minutes, M _obs = 511 (M + 1) (LCMS conditions: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate : 2.75 mL / min, gradient: 100% eluent A to 100% eluent B for 2 minutes, and 100% eluent B plateau for 1 minute, eluent A is H ₂ O (0.05% TFA) Yes, eluent B is CH ₃ CN / H ₂ O / TFA (80/20 / 0.05).

実施例１５（３３ｍｇ、０．０８ｍｍｏｌ）、製造例２９（５７．８ｍｇ、０．１２ｍｍｏｌ）、ＴＥＡ（１６．７μＬ、０．１２ｍｍｏｌ）およびＰＳ−ＤＭＡＰ（Argonaut、５ｍｇ）混合物を、ＲＴで終夜撹拌した。上記標題化合物（４．１ｍｇ）を、逆相ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの５／９５／０．０５〜ＣＨ_３ＣＮ／Ｈ_２Ｏ／ＴＦＡの８０／２０／０．０５の勾配を使用）によって精製後に、得た。保持時間は１．４９分である、５７３（Ｍ＋1）（LCMS条件：LC Micromass platform (APCI＋, DAD (210-400 nm))、カラム：TSK gel Super ODS 4.6 mm ID × 5 cm、流速：2.75 mL／分、勾配：１００％溶出液Ａ〜１００％溶出液Ｂ。 Example 283
4-{(5S ^* , 9R ^* )-3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-7- [2- (1H-tetrazol-5-yl) benzyl] -1, 3,7-triazaspiro [4.4] non-9-yl} benzonitrile

A mixture of Example 15 (33 mg, 0.08 mmol), Preparation 29 (57.8 mg, 0.12 mmol), TEA (16.7 μL, 0.12 mmol) and PS-DMAP (Argonaut, 5 mg) was stirred at RT overnight. did. The title compound (4.1 mg), reverse phase _{HPLC (CH 3 CN / H 2} O / TFA for _{5/95 / 0.05~CH 3 CN /} H 2 of O / TFA 80/20 / 0.05 Obtained after purification by gradient). Retention time is 1.49 minutes, 573 (M + 1) (LCMS conditions: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 2.75 mL / Min, gradient: 100% eluent A to 100% eluent B.

上記標題化合物は、実施例２８３について記載する方法を用いて、実施例１５および製造例３１から得た。保持時間は１．４７分である、Ｍ_ｏｂｓ＝５６４／５６６ (ＭおよびＭ＋２）（LCMS条件：LC Micromass platform (APCI＋, DAD (210-400 nm))、カラム：TSK gel Super ODS 4.6 mm ID × 5 cm、流速：2.75 mL／分、勾配：１００％溶出液Ａ〜１００％溶出液Ｂ。 Example 284
6-[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4. 4] Nona-7-ylmethyl] nicotinic acid methyl ester

The title compound was obtained from Example 15 and Preparation 31 using the method described for Example 283. Retention time is 1.47 minutes, M _obs = 564/566 (M and M + 2) (LCMS conditions: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 2.75 mL / min, gradient: 100% eluent A to 100% eluent B.

上記標題化合物を、実施例５９に記載する方法を用いて実施例２８４から得た。保持時間は１．３８分である、Ｍ_ｏｂｓ＝５５０／５５２（ＭおよびＭ＋２）（LCMS条件：LC Micromass platform (APCI＋, DAD (210-400 nm))、カラム：TSK gel Super ODS 4.6 mm ID × 5 cm、流速：2.75 mL／分、勾配：１００％溶出液Ａ〜１００％溶出液Ｂ。 Example 285
6-[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4. 4] Nona-7-ylmethyl] nicotinic acid

The title compound was obtained from Example 284 using the method described in Example 59. Retention time is 1.38 minutes, M _obs = 550/552 (M and M + 2) (LCMS conditions: LC Micromass platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate: 2.75 mL / min, gradient: 100% eluent A to 100% eluent B.

上記標題化合物を、実施例１５について記載の方法を用いて、実施例２７９から得た。白色固体、ｍｐ＝２０２℃。 Example 286
4-[(5S ^* , 9R ^* )-3- (2,6-dichloropyridin-4-yl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4.4] nona 7-ylmethyl] benzonitrile

The title compound was obtained from Example 279 using the method described for Example 15. White solid, mp = 202 ° C.

実施例２８７は、実施例３７に記載の還元的アミノ化方法によって実施例１５および製造例３２から製造した。保持時間は８．４０分である、Ｍ_ｏｂｓ＝５８０（M＋1 LCMS）条件：HP 1100 MSD platform (APCI＋, DAD (210-400 nm))、カラム：TSK gel Super ODS 4.6 mm ID × 5 cm、流速：1 mL／分、勾配：５％〜９５％溶出液Ｂを１５分間、および９５％溶出液Ｂのプラトーを５分間、溶出液ＡはＨ_２Ｏ（０．１％ギ酸アンモニウム）であり、溶出液ＢはＣＨ_３ＣＮである。 Example 287
4-{(5S ^* , 9R ^* )-3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-7- [4- (1H-tetrazol-5-yl) -thiophen-2- Ylmethyl] -1,3,7-triazaspiro [4.4] non-9-ylmethyl] benzonitrile

Example 287 was prepared from Example 15 and Preparation 32 by the reductive amination method described in Example 37. Retention time is 8.40 minutes, M _obs = 580 (M + 1 LCMS) conditions: HP 1100 MSD platform (APCI +, DAD (210-400 nm)), column: TSK gel Super ODS 4.6 mm ID × 5 cm, flow rate : 1 mL / min, gradient: 5% to 95% eluent B for 15 minutes, and 95% eluent B plateau for 5 minutes, eluent A is H ₂ O (0.1% ammonium formate) Eluent B is CH ₃ CN.

実施例２８８は、実施例２８７に記載する通り、適当なアルデヒドを用いて製造した。白色固体、ｍｐ＝２３０〜２３２℃。 Example 288
5-[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (2,6-dichloropyridin-4-yl) -1-methyl-2,4-dioxo-1,3,7 -Triazaspiro [4.4] non-7-ylmethyl] thiophene-3-carboxylic acid

Example 288 was prepared using the appropriate aldehyde as described in Example 287. White solid, mp = 230-232 ° C.

実施例２８９は、実施例２８７に記載する通り、適当なアルデヒドを用いて製造した。オフホワイト色固体、ｍｐ＝２５２℃。 Example 289
5-[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (2,6-dichloropyridin-4-yl) -1-methyl-2,4-dioxo-1,3,7 -Triazaspiro [4.4] non-7-ylmethyl] thiophene-2-carboxylic acid

Example 289 was prepared using the appropriate aldehyde as described in Example 287. Off-white solid, mp = 252 ° C.

５−[(５Ｓ^＊,９Ｒ^＊)−９−(４−シアノフェニル)−３−(３,５−ジクロロフェニル)−１−メチル−２,４−ジオキソ−１,３,７−トリアザスピロ[４.４]ノナ−７−イルメチル]チオフェン−３−カルボン酸（実施例３７）（０．１５０ｇ、０．２７ｍｍｏｌ）のＤＣＭ／ＭｅＯＨ（５：１ｍＬ）溶液に、トリメチルシリルジアゾメタン（２．０Ｍ ヘキサン溶液、０．３３ｍＬ、０．６７ｍｍｏｌ）をＲＴで３分間かけて加えた。該反応混合物をＲＴで２０分間撹拌し、酢酸（約１０滴）をゆっくりと加えることによってクエンチし、そしてＤＣＭ（２０ｍＬ）および飽和炭酸水素ナトリウム水溶液（１５ｍＬ）の間で分配した。該ＤＣＭ相をブライン（２０ｍＬ）で洗浄し、硫酸ナトリウムを用いて乾燥し、そして濃縮して濃厚油状物を得た。ＬＣ保持時間は３．３４分である。使用するカラム：YMC S5 combiscreen ODS 4.6 × 50 mm（４分間の勾配）；溶媒Ａは１０％ＭｅＯＨ、９０％Ｈ_２Ｏおよび０．２％Ｈ_３ＰＯ_４であり；溶媒Ｂは９０％ＭｅＯＨ、１０％Ｈ_２Ｏおよび０．２％Ｈ_３ＰＯ_４である。 Example 290
5-[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4. 4] Nona-7-ylmethyl] thiophene-3-carboxylic acid methyl ester

5-[(5S ^* , 9R ^* )-9- (4-cyanophenyl) -3- (3,5-dichlorophenyl) -1-methyl-2,4-dioxo-1,3,7-triazaspiro [4. 4] Nona-7-ylmethyl] thiophene-3-carboxylic acid (Example 37) (0.150 g, 0.27 mmol) in DCM / MeOH (5: 1 mL) was added to trimethylsilyldiazomethane (2.0 M hexane solution, 0 .33 mL, 0.67 mmol) was added over 3 min at RT. The reaction mixture was stirred at RT for 20 min, quenched by the slow addition of acetic acid (ca. 10 drops) and partitioned between DCM (20 mL) and saturated aqueous sodium bicarbonate (15 mL). The DCM phase was washed with brine (20 mL), dried with sodium sulfate and concentrated to give a thick oil. The LC retention time is 3.34 minutes. Column used: YMC S5 combiscreen ODS 4.6 × 50 mm (4 minute gradient); solvent A is 10% MeOH, 90% H ₂ O and 0.2% H ₃ PO ₄ ; solvent B is 90% MeOH, 10% _{H 2} O, and a _0.2% H 3 PO _4.

Claims (25)

Formula (I):

Or an enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[Where:
L and K are independently O or S;
Z is N or CR _4b ;
Ar is aryl or heteroaryl;
G is bonded to ring A at the T or M position, and (i) when bonded to a carbon atom of ring A, G is a bond, —O—, —N—, —S—, C _{1. to 4} alkylene, substituted C _{1 to 4} alkylene or a divalent alkoxy, alkylthio, aminoalkyl, sulfonyl, sulfonamidyl, or selected from an acyl or alkoxycarbonyl; or
(Ii) when bound to the nitrogen atom of ring A, G is a bond, C _1-4 alkylene, substituted C _1-4 alkylene, divalent acyl or alkoxycarbonyl, or divalent alkoxy, alkylthio, amino Selected from alkyl, sulfonyl or sulfonamidyl, and in case (ii) each G group has at least one carbon atom directly attached to ring A;
J has a substituted or unsubstituted _C1-3 alkylene, a substituted or unsubstituted _C2-3 alkenylene, an unsubstituted _C1-2 heteroalkylene, or 1-2 carbon atoms in the heteroalkylene straight chain. Substituted heteroalkylene;
T is T ₁ when G-Ar is bound to T; and T is G ₂ when G-Ar is bound to M;
M is M ₁ when G-Ar binds M; and M ₂ when G-Ar binds T;
T ₁ and M ₁ are selected from —N— or —C (R ₅ ) —;
J, M and T are 3 to 6 membered saturated or partially unsaturated cycloalkyl or heterocycle having 1 to 4 heteroatoms (wherein two adjacent heteroatoms of the heterocycle A are T ₂ and M ₂ are —O—, —S—, —N (R ₆ ) —, provided that they are selected to define -N =, - S (= O ) -, - SO 2 -, - NHSO 2 -, or -C _(R 7 _{R 8)} - is selected from;
R ₂ is hydrogen, alkyl, substituted alkyl, OR ₁₂ , NR ₁₂ R ₁₃ , C (═O) R ₁₂ , CO ₂ R ₁₂ , C (═O) NR ₁₂ R ₁₃ , NR ₁₂ C (═O) R ₁₃ , NR ₁₂ C (═O) OR ₁₃ , S (O) _p R _13a , NR ₁₂ SO ₂ R _13a , SO ₂ NR ₁₂ R ₁₃ , cycloalkyl, heterocyclo, aryl, or heteroaryl;
R _4a , R _4b and R _4c are independently hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, nitro, cyano, SR ₁₄ , OR ₁₄ , NR ₁₄ R ₁₅ , NR ₁₄ C (═O) R ₁₅ , CO ₂ R ₁₄ , C (═O) R ₁₄ , —C (═O) NR ₁₄ R ₁₅ , aryl, heterocyclo, cycloalkyl, or heteroaryl;
R ₆ is independently hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, alkenyl, substituted alkenyl, aminoalkyl, alkylthio, C (═O) H, acyl, amide, alkoxycarbonyl, sulfonyl, sulfonamidyl, cycloalkyl , Heterocyclo, aryl or heteroaryl;
R ₅ , R ₇ and R ₈ are
(I) Independently, hydrogen, alkyl, substituted alkyl, halogen, nitro, cyano, hydroxy, alkoxy, alkenyl, substituted alkenyl, aminoalkyl, alkylthio, C (═O) H, acyl, CO ₂ H, amide, alkoxy Selected from carbonyl, sulfonyl, sulfonamidyl, cycloalkyl, heterocyclo, aryl, or heteroaryl;
(Ii) R ₇ and R ₈ can be taken together to form a double bond (defining a keto (═O) group) with a cycloalkyl, heterocycle, or oxygen atom;
(Iii) one of R ₅ or R ₈ can be a bond such that there is a double bond between T and M, respectively, or between M and J, so that ring A is partially unsaturated Is;
R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are
(I) each independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo; or
(Ii) R ₁₂ is taken together with R ₁₃ and / or R ₁₄ is taken together with R ₁₅ to form a heteroaryl or heterocycle;
R _13a is selected from alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo; and
p is Ri 1 or 2 der; wherein
The substituted alkyl is halo, alkenyl, substituted alkenyl, alkynyl, nitro, cyano, oxo (═O), OR _a , SR _a , (═S), —NR _a R _b , —N (alkyl) ₃ ⁺ , _{-NR a SO 2, -NR a SO} 2 R c, -SO 2 R c, -SO 2 NR a R b, -SO 2 NR a C (= O) R b, SO 3 H, -PO (OH) ₂ , —C (═O) R _a , —CO ₂ R _a , —C (═O) NR _a R _b , —C (═O) (C _1-4 alkylene) NR _a R _b , —C (= O) NR _a (SO ₂ ) R _b , —CO ₂ (C _1-4 alkylene) NR _a R _b , —NR _a C (═O) R _b , —NR _a CO ₂ R _b , —NR _a (C _{1-4 alkylene) CO 2 R b, = N} -OH, = N-O- alkyl, aryl, cycloalkyl, heterocyclo and / or heteroaryl An alkyl group having 1, 2 or 3 substituents selected from the group consisting of Le, wherein said _{R a} and _{R b} are hydrogen, alkyl, _alkenyl, CO _{2 H,} CO 2 (alkyl), C _{3 to 7} cycloalkyl, phenyl, forming benzyl, phenylethyl, naphthyl or 4-7 membered heterocyclo or 5-6 membered or selected from heteroaryl, or heterocyclo or heteroaryl bonded to the same nitrogen atom, And R _c is selected from the same groups as R _a and R _b , but not hydrogen; each of R _a and R _{b in} the case of other than hydrogen , and each R _c is optionally R _a , R _b It has a _b and / or 1-3 further substituents attached at either on an available carbon atom or nitrogen atom of R _c, the substituents, (C _{1 to 6)} alkyl, (C ₆₎ alkenyl, hydroxy, halogen, cyano, _{nitro, CF} 3, O _(C 1~6 _{alkyl), OCF 3, C (=} O) H, C (= O) (C 1~6 alkyl), CO _{2 H,} CO _{2 (C} 1~6 _alkyl), NHCO _{2 (C} 1~6 _alkyl), - S _(C 1~6 _{alkyl), - NH 2, NH (} C 1~6 _alkyl), N _(C 1~ ₆ alkyl) ₂ , N (CH ₃ ) ₃ ⁺ , SO ₂ (C _1-6 alkyl), C (═O) (C _1-4 alkylene) NH ₂ , C (═O) (C _1-4 alkylene) NH (alkyl), C (═O) (C _1-4 alkylene) N (C _1-4 alkyl) ₂ , C _3-7 cycloalkyl, phenyl, benzyl, phenylethyl, phenyloxy, benzyloxy, naphthyl, 4 Selected from the group consisting of ˜7 membered heterocyclo, or 5-6 membered heteroaryl;
The substituted alkenyl, the substituted alkylene, the substituted C _1-4 alkylene, the substituted C _1-3 alkylene, and the substituted C _2-3 alkenylene are each one to three substituents as defined above for the substituted alkyl group. Alkenyl, alkylene, C _1-4 alkylene, C _1-3 alkylene, or C _2-3 alkenylene substituted with:
The substituted heteroalkylene is a heteroalkylene group in which at least one nitrogen atom or carbon atom in the heteroalkylene chain is bonded to or substituted with a group other than hydrogen, and the carbon atom in the heteroalkylene chain is Which can be substituted with a group selected from the above-mentioned substituents for a substituted alkyl group or with a further alkyl group or a substituted alkyl group, wherein the nitrogen atom of the heteroalkylene chain is alkyl, alkenyl, alkynyl, cyano or A ₁ -Q and it could be substituted by a group selected from -A ₂ -R _h, wherein, _{a 1} is a _bond, a _{C 1 to 2} alkylene or _{C 2 to 3} alkenylene, Q is bond, -C (= O) -, _{-C (= O) NR d -} , - C (= S) NR d -, - SO 2 -, - SO 2 NR d -, - CO 2 -, or _-NR d CO ₂ - a is, _{a 2} The _{bond, C 1 to 3 alkylene, C 2 to 3 alkenylene, -C 1 to 4} alkylene _-NR d _-, - _C 1~4 alkylene _{-NR d C (= O) -} , - C 1~4 alkylene -S -, _{- C 1-4} alkylene -SO ₂ -, or _-C a _1-4 alkylene -O-, wherein said _{a 2} alkylene groups are branched or straight chain, this compound optionally substituted Substituted as defined for alkylene, R _h is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclo, or cycloalkyl, and R _d is hydrogen, alkyl, or selected from substituted alkyl, provided that the substituted heteroalkylene, when a _{1, Q} and a ₂ are each bond R _h is not hydrogen. ] G is a bond;
Ar is aryl or heteroaryl substituted with ₁ to 3 R ₁ ;
R ₁ is alkyl, substituted alkyl, halogen, cyano, nitro, OR ₁₀ , NR ₁₀ R ₁₁ , C (═O) R ₁₀ , CO ₂ R ₁₀ , C (═O) NR ₁₀ R ₁₁ , NR ₁₀ C ( ═O) R ₁₁ , NR ₁₀ C (═O) OR ₁₁ , SR ₁₀ , S (O) _o R _10a , NR ₁₀ SO ₂ R _10a , NHCH (alkyl) CO ₂ R ₁₀ , SO ₂ NR ₁₀ R ₁₁ , Selected from cycloalkyl, heterocyclo, aryl, or heteroaryl;
R ₁₀ and R ₁₁ are
(I) each independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo; or
(Ii) R ₁₀ together with R ₁₁ forms a heteroaryl or heterocyclo;
R _10a is alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo; and
o is 1 or 2;
2. A compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or enantiomer thereof. J is C _1-3 alkylene, C _2-3 alkenylene, or C _1-2 heteroalkylene, optionally substituted with 1-2 R ₉ ;
R ₉ is -A ₁ -QA ₂ -R ₁₆ ;
A ₁ is a bond, C _1-2 alkylene, or C _2-3 alkenylene;
Q is a bond, —C (═O) —, —C (═O) NR ₁₇ —, —C (═S) NR ₁₇ —, —SO ₂ —, —SO ₂ NR ₁₇ —, —CO ₂ —, Or —NR ₁₇ CO ₂ —;
A ₂ is a _{bond, C 1 to 3 alkylene, C 2 to 3 alkenylene, -C 1 to 4} alkylene _-NR 17 _-, - _C 1~4 alkylene _{-NR 17 C (= O) -} , - C 1~4 Alkylene-S—, —C _1-4 alkylene-SO ₂ —, or —C _1-4 alkylene-O—, wherein the A ₂ alkylene group is branched or straight chain, and optionally CO _2. Selected from H, —CO ₂ (C _1-4 alkyl), —S (C _1-4 alkyl), NH ₂ , —NH (C _1-4 alkyl), or —N (C _1-4 alkyl) ₂ Substituted with a group;
R ₁₆ is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, cycloalkyl, or heterocyclo; and
R ₁₇ is hydrogen or alkyl.
2. A compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or enantiomer thereof. R ₁₆ is selected from cycloalkyl, heterocyclo, aryl, or heteroaryl optionally substituted with 1-3 of R ₁₈ ;
R ₁₈ is C _1-6 alkyl, substituted C _1-6 alkyl, halogen, cyano, nitro, OR ₂₀ , NR ₂₀ R ₂₁ , C (═O) R ₂₀ , CO ₂ R ₂₀ , C (═O) NR. _{20 R 21, C (= O} ) NR 20 SO 2 R 20a, NR 20 C (= O) R 21, NR 20 C (= O) OR 21, SR 20, S (O) u R 20a, NR 20 SO Selected from ₂ R _20a , NHCH (alkyl) CO ₂ R ₂₀ , SO ₂ NR ₂₀ R ₂₁ , C _3-7 cycloalkyl, phenyl, 4-7 membered heterocyclo, or 5-6 membered heteroaryl; _{A 3-7} cycloalkyl group, a phenyl group, a 4-7 membered heterocyclo group, or a 5-6 membered heteroaryl group is optionally substituted with 1-2 R ₂₂ ;
R ₂₀ and R ₂₁ are selected from hydrogen, alkyl, alkenyl, C _3-7 cycloalkyl, phenyl, benzyl, phenylethyl, naphthyl, 4-7 membered heterocyclo, or 5-6 membered heteroaryl; or ,
Bonded to the same nitrogen atom together to form a heterocyclo or heteroaryl (where each R ₂₀ and R ₂₁ is optionally substituted with 1 to 2 R ₂₂ );
R _20a is hydrogen, alkyl, alkenyl, CO ₂ H, CO ₂ (alkyl), C _3-7 cycloalkyl, phenyl, benzyl, phenylethyl, naphthyl, 4-7 membered heterocyclo, or 5-6 membered heterocycle Selected from aryl, wherein each R _20a is optionally substituted with 1-2 R ₂₂ ; and
R ₂₂ is (C _1-4 ) alkyl, (C _2-4 ) alkenyl, hydroxy, cyano, CF ₃ , O (C _1-4 alkyl), OCF ₃ , C (═O) H, C (═O ) _{(C 1 to 4 alkyl), CO 2 H, CO 2} (C 1~4 _alkyl), NHCO _{2 (C} 1~4 _alkyl), - S _(C 1~4 _{alkyl), - NH 2, NH (} C _1-4 alkyl), N (C _1-4 alkyl) ₂ , N (CH ₃ ) ₃ ⁺ , SO ₂ (C _1-4 alkyl), C (═O) (C _1-4 alkylene) NH ₂ , C (═O) (C _1-4 alkylene) NH (alkyl) or C (═O) (C _1-4 alkylene) N (C _1-4 alkyl) ₂ , wherein
The substituted C _1-6 alkyl is a C _1-6 alkyl group substituted with 1 to 3 substituents as defined in claim 1 for the substituted alkyl group.
4. A compound according to claim 3, or a pharmaceutically acceptable salt, hydrate or enantiomer thereof. Ar is the formula:

Is;
T ₁ and M ₁ are selected from —N— or —CH—; and T ₂ and M ₂ are O, S, NH, S (═O), SO ₂ , NHSO ₂ , —C (═O) —, Or —CH ₂ —;
J is —C _2-3 alkylene optionally substituted with 1-2 R _9, — (CH ₂ ) _y —NH—, or — (CH ₂ ) _y —NR ₉ — as appropriate;
R _1a and R _1b are independently halogen, C _1-4 alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, —CO ₂ H, —C (═O) H, —CO ₂ alkyl, — C (= O) alkyl, -C (= O) NH ( CH 2) 1~4 CO 2 H, -C (= O) NH (CH 2) 1~4 CO 2 ( alkyl), or S (O) Is selected from ₂ alkyls;
Optionally substituted (wherein the substituents are halogen, C _1-4 alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, —CO ₂ H, —C (═O) H, CO ₂ alkyl, And / or -C (= O) alkyl) is selected from phenyl, benzyl, phenyloxy, benzyloxy, or heteroaryl;
Two R _1b groups taken together or one R _{1b taken} together with R _1a to form a fused benzo ring;
R _4a and R _4c are selected from halogen, alkyl, cyano, haloalkyl, haloalkoxy, nitro, aryloxy, or arylthio;
R _4b is hydrogen, halogen, alkyl, substituted alkyl, nitro, cyano, hydroxy, alkoxy, haloalkoxy, phenyloxy, —CO ₂ H, —C (═O) H, —NH (alkyl), —N (alkyl ) ₂ , —CO ₂ alkyl, —C (═O) alkyl, alkylthio, —C (═O) NH (CH ₂ ) _1-4 CO ₂ H, —C (═O) NH (CH ₂ ) _1-4 CO ₂ (alkyl), aryl, heteroaryl or heterocyclo, wherein each of the aryl, heteroaryl and heterocyclo groups is optionally 1-2 halogen, C _1-4 alkyl, OMe, CF ₃ , Substituted with CN, OCF ₃ , CO ₂ H, C (═O) H, CO ₂ alkyl and / or C (═O) alkyl;
n is 0, 1 or 2; and
y is 0, 1 or 2;
5. A compound according to claim 4, or a pharmaceutically acceptable salt, hydrate or enantiomer thereof. formula:

The compound of Claim 5 shown by these, or its pharmaceutically acceptable salt, hydrate, or its enantiomer. 7. A compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein R _1a is hydrogen or cyano and R _4a and R _4c are independently selected from halogen, alkyl, cyano, trifluoromethyl or nitro. Salt, hydrate or enantiomer. Formula (Ie):

[Where:
R _1a and R _1b are independently halogen, C _1-4 alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, —CO ₂ H, —C (═O) H, —CO ₂ alkyl, — C (= O) alkyl, -C (= O) NH ( CH 2) 1~4 CO 2 H, -C (= O) NH (CH 2) 1~4 CO 2 ( alkyl), or S (O) Selected from ₂ alkyls;
Optionally substituted (wherein the substituents are halogen, C _1-4 alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, —CO ₂ H, —C (═O) H, —CO _2. Selected from phenyl, benzyl, phenyloxy, benzyloxy, or heteroaryl (which is alkyl and / or —C (═O) alkyl); or
Two R _1b groups taken together or one R _{1b taken} together with R _1a to form a fused benzo ring; and
n is 0, 1 or 2]
Or a pharmaceutically acceptable salt, hydrate or enantiomer thereof. R _1a is halogen, cyano, nitro, trifluoromethyl, OCF ₃ , aryl, or heteroaryl;
R _1b is halogen, C _1-4 alkyl, cyano, nitro, —CO ₂ H, —C (═O) H, —CO ₂ alkyl, or —C (═O) alkyl;
R ₂ is _{hydrogen, C 1-6} alkyl, or there _{C 1 to 6} alkyl substituted with CO ₂ H or CO _{2 (C 1 to 4} alkyl);
R ₉ is hydrogen, C _1-10 alkyl, substituted C _1-10 alkyl, C _2-10 alkenyl, substituted C _2-10 alkenyl, C _3-6 cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, — (CH _{2) s} phenyl, - (CH _{2) s} tetrazolyl, - (CH _{2) s} pyridyl, - (CH _{2) s} thienyl, - (CH _{2) s} carbazolyl, - (CH _{2) s} indolyl, - (CH _{2) s} furyl, - (CH _{2) s} quinolyl, - (CH _{2) s} C _{3 to 6} cycloalkyl, - (CH _{2) s} thiazolyl, - (CH _{2) s} pyrrolyl, - (CH _{2) s} imidazolyl, - ( CH _{2) s} isoxazolyl, - (CH _{2) s} benzofuryl, - (CH _{2) s} pyrazolyl, -C (= O) H, -C (= O) ( alkyl), - C (= O) C 1~10 Alkyl, -C (= O) phenyl, -C (= O) Perijiru, -C (= O) morpholinyl, -C (= O) _{C 3 to 6} cycloalkyl, -C (= O) pyrrolidinyl, -C (= O) quinolyl, -C (= O) imidazolyl, -C ( = O) pyrazolyl, -C (= O) thiazolyl, -C (= O) quinoxalinyl, -C (= O) pyridyl, -C (= O) -1,2,5,6-tetrahydropyridyl, -C ( ═O) benzothiazolyl, —C (═O) benzotriazolyl, —C (═O) benzodioxanyl, —C (═O) benzooxadiazolyl, —C (═O) 1,2,3, 4- tetrahydroquinolyl, -C (= O) thieno-pyrazolyl, -C (= O) (CH 2) s tetrazolyl, -C (= O) (CH 2) s pyridyl, -C (= O) (CH 2 ) _s phenyl, -C (= O) (CH 2) s pyrrolidinyl, -C (= O) (CH 2) s piperidyl, -C (= O) CH = CH ( phenyl), - C (= O) CH = CH (pyridyl), - C (= O) CH 2 O ( alkyl), - C (= O) CH 2 S ( alkyl), - C (= O) CH 2 S ( pyridyl), - C (= O) CH ₂ SO ₂ (alkyl), —C (═O) CH ₂ SO ₂ (phenyl), —C (═O) CH ₂ NH (phenyl), —C (═O) CH ₂ NH (benzyl), —C (═O) CH ₂ NH (thiazolyl), —C (═O) CH ₂ NHC (═O) pyridyl, —C (═O) CH ₂ NHC (═O) phenyl, — (CH ₂ ) _t SO ₂ ( _{alkyl), - (CH 2) t} SO 2 ( _{phenyl), - (CH 2) t} SO 2 ( _{thienyl), - (CH 2) t} SO 2 ( _{imidazolyl), - (CH 2) t} SO 2 ( furyl) , (CH ₂ ) _t SO ₂ (pyrrolyl), SO ₂ NH (phenyl), —C (═S) NH ₂ , —C (═S) NH (alkyl), —C (═S) NH (phenyl), _{- (CH 2) C (=} O) pyrrolidinyl , — (CH ₂ ) C (═O) piperidyl, — (CH ₂ ) C (═O) piperazinyl, —CO ₂ (alkyl), —CO ₂ (phenyl), —CO ₂ (benzyl), NHCO ₂ (alkyl) ), — (CH ₂ ) _t C (═O) NH (phenyl), — (CH ₂ ) _t C (═O) NH (piperidyl), — (CH ₂ ) _t C (═O) NH (thienyl), _{- (CH 2) t C (} = O) NH ( thiazolyl), _{- (CH 2) t C (} = O) NH ( cyclopentyl), _{- (CH 2) t C (} = O) NH ( cyclopentenyl), - (CH ₂ ) _t C (═O) NH (benzyl), — (CH ₂ ) _t C (═O) NH (pyrrolidinyl), — (CH ₂ ) _t C (═O) NH (piperazinyl), — (CH _{2) t C (= O)} NH 2, - (CH 2) t C (= O) NH ( _{alkyl), - (CH 2) t} C (= O) N ( _{alkyl) 2, - (CH 2)} t _{C (= O) N (C} 1~4 alkyl) (phenyl), - ( _{H 2) t C (= O} ) N (C 1~4 alkyl) _{(thienyl), - (CH 2) t} C (= O) N (C 1~4 alkyl) (thiazolyl), - (CH _{2) t} C (═O) N (C _1-4 alkyl) (benzyl), or — (CH ₂ ) _t C (═O) N (C _1-4 alkyl) CO ₂ (alkyl), wherein each R ₉ is optionally substituted with 1 to 2 R ₁₈ ;
R ₁₈ is — (CH ₂ ) _q halogen, — (CH ₂ ) _q nitro, — (CH ₂ ) _q cyano, — (CH ₂ ) _q haloalkyl, — (CH ₂ ) _q haloalkoxy, — (CH ₂ ) _q SR ₂₄ , C _3-7 cycloalkyl, —SO ₂ R ₂₄ , —OR ₂₄ , — (CH ₂ ) _q CO ₂ R ₂₄ , — (CH ₂ ) _q NR ₂₄ R ₂₅ , — (CH ₂ ) _q NHCO _{2 R 24, -C (= O} ) NH-SO 2 R 24, -C (= O) (CH 2) q NR 24 R 25, -O (CH 2) r NR 24 R 25, -C (= O ) R ₂₄ , — (CH ₂ ) _q R ₂₄ , or —C _1-4 alkyl or —C _2-4 alkenyl optionally substituted with CO ₂ R ₂₄ ;
When R ₂₄ is bonded to a sulfonyl group as in —SO ₂ R ₂₄ , R ₂₄ is not hydrogen, and R ₂₄ is hydrogen, alkyl, phenyl, benzyl, C _3-7 cycloalkyl, 5 or It is selected from 6-membered heteroaryl or 4- to 7-membered heterocyclo, which are optionally substituted by 1 to 2 substituents (the substituents are C _1-4 alkyl, halogen, hydroxy, trifluoromethyl, trifluoromethoxy). it is substituted with _{-CO 2 H,} CO 2 _{C 1~4 alkyl, C 1 to 4} alkoxy, -S _{(C 1 to 4} alkyl), amino, and / or amino _{C 1 to 4} alkyl);
R ₂₅ is selected from hydrogen or alkyl;
n is 0, 1 or 2;
p is 1 or 2;
q is 0, 1, 2, 3 or 4;
r is 1, 2, 3 or 4;
s is 0, 1, 2, 3 or 4; and
t is, Ri 1, 2, 3, or 4 der, here,
The substituted C _1-10 alkyl and the substituted C _2-10 alkenyl are each a C _1-10 alkyl group and C ₂ substituted with 1 to 3 substituents as defined in claim 1 for the substituted alkyl group. _{A -10} alkenyl group,
9. A compound according to claim 8, or a pharmaceutically acceptable salt, hydrate or enantiomer thereof. J is the formula:

Chosen from;
A ₁ is a bond, C _1-2 alkylene, or C _2-3 alkenylene;
Q is a bond, —C (═O) —, —C (═O) NR ₁₇ —, —SO ₂ —, —CO ₂ —, or NR ₁₇ CO ₂ —;
A ₂ is a _{bond, C 1 to 3 alkylene, C 2 to 3 alkenylene, -C 1 to 4} alkylene _{-NR 17 -,} - _C 1~4 alkylene _{-NR 17 C (= O) -} , - C 1~4 Alkylene-S—, —C _1-4 alkylene-SO ₂ —, or —C _1-4 alkylene-O—, wherein the A ₂ alkylene group is branched or straight chain, and CO ₂ H, —CO ₂ (C _1-4 alkyl), —S (C _1-4 alkyl), NH ₂ , —NH (C _1-4 alkyl), or —N (C _1-4 alkyl) _{2 as} appropriate. Substituted with a group selected from:
R ₁₇ is hydrogen or alkyl;
R ₁₈ and R ₁₉ are hydrogen, (C _1-6 ) alkyl, (C _2-6 ) alkenyl, CO ₂ H, CO ₂ (C _1-6 alkyl), C (═O) H, C (═O ) _{(C 1 to 6} alkyl), halogen, cyano, hydroxy, _{(C 1 to 4)} alkoxy, _{(C 1 to 4)} haloalkyl, _{(C 1 to 4) haloalkoxy, NH} 2, _{NH (C} 1~4 alkyl ), N (C _1-4 alkyl) ₂ , N (C _1-4 alkyl) ₃ ⁺ , —C (═O) (CH ₂ ) NH ₂ , —NHCO ₂ (C _1-4 alkyl), —C ( ═O) selected from NHSO ₂ (C _1-4 alkyl), SO ₂ (C _1-4 alkyl), phenyl, C _3-7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclo. Where R ₁₈ and R ₁₉ are each suitably 1 or 2 (C _1-4 ) alkyl, (C _2-4 ) alkenyl. , CO ₂ H, CO ₂ (C _1-4 alkyl), C (═O) H, C (═O) (C _1-4 alkyl), halogen, cyano, hydroxy, (C _1-4 ) alkoxy, tri fluoromethyl, _{trifluoromethoxy, NH} 2, _{NH (C} 1~4 alkyl), N _{(C 1 to 4 alkyl) 2,} N _{(C 1~4 ^{alkyl) 3 +, -C (= O}} ) (CH 2) NH _2, substituted by -NHCO _{2 (C 1 to 4} alkyl), and / or SO _{2 (C 1 to 4} alkyl);
f is 0, 1, 2, or 3; and
g is -1, 0, 1, or 2.
2. A compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or enantiomer thereof. The compound of claim 1, wherein Z is CR _4b , or a pharmaceutically acceptable salt, hydrate or enantiomer thereof. J

An expression selected from one of the following:

Or a pharmaceutically acceptable salt, hydrate or enantiomer thereof. formula:

[Where:
R _1a is halogen, cyano, nitro, trifluoromethyl, OCF ₃ , aryl, or heteroaryl;
R _1b is halogen, C _1-4 alkyl, cyano, nitro, —CO ₂ H, —C (═O) H, —CO ₂ alkyl, or —C (═O) alkyl;
R ₂ is _{hydrogen, C 1-6} alkyl, or there _{C 1 to 6} alkyl substituted with CO ₂ H or CO _{2 (C 1 to 4} alkyl);
R ₁₈ is (C _1-4 ) alkyl, CO ₂ H, CO ₂ (C _1-4 alkyl), C (═O) H, C (═O) (C _1-4 alkyl), halogen, cyano, hydroxy, _{(C 1 to 4)} alkoxy, _{(C 1 to 4)} haloalkyl, _{(C 1 to 4) haloalkoxy, NH} 2, _{NH (C} 1~4 _alkyl), N _(C 1~4 _alkyl) 2, N (C _1-4 alkyl) ₃ ⁺ , —C (═O) (CH ₂ ) NH ₂ , —NHCO ₂ (C _1-4 alkyl), —C (═O) NHSO ₂ (C _1-4 alkyl), Selected from SO ₂ (C _1-4 alkyl), thienyl, tetrazolyl, triazolyl, pyrazolyl, or imidazolyl;
f is 0, 1, 2 or 3; and
n is 0 or 1]
Or a pharmaceutically acceptable salt, hydrate or enantiomer thereof. formula:

[Where:
R _1a is halogen, cyano, nitro, trifluoromethyl, OCF ₃ , aryl, or heteroaryl;
R _1b is halogen, C _1-4 alkyl, cyano, nitro, —CO ₂ H, —C (═O) H, —CO ₂ alkyl, or —C (═O) alkyl;
R ₂ is _{hydrogen, C 1-6} alkyl, or there _{C 1 to 6} alkyl substituted with CO ₂ H or CO _{2 (C 1 to 4} alkyl);
R ₁₈ is (C _1-4 ) alkyl, CO ₂ H, CO ₂ (C _1-4 alkyl), C (═O) H, C (═O) (C _1-4 alkyl), halogen, cyano, hydroxy, _{(C 1 to 4)} alkoxy, _{(C 1 to 4)} haloalkyl, _{(C 1 to 4) haloalkoxy, NH} 2, _{NH (C} 1~4 _alkyl), N _(C 1~4 _alkyl) 2, N (C _1-4 alkyl) ₃ ⁺ , —C (═O) (CH ₂ ) NH ₂ , —NHCO ₂ (C _1-4 alkyl), —C (═O) NHSO ₂ (C _1-4 alkyl), Selected from SO ₂ (C _1-4 alkyl), thienyl, tetrazolyl, triazolyl, pyrazolyl, or imidazolyl;
f is 0, 1, 2 or 3; and
n is 0 or 1]
Or a pharmaceutically acceptable salt, hydrate or enantiomer thereof. formula:

[Where:
L and K are independently O or S;
Z is N or CR _4b ;
J is selected from — (CR _9a R _9c ) _x or — (CR _9a R _9c ) _y —NR _9c — (CR _9a R _9b ) _z —,
x is 1, 2 or 3, y is 0, 1 or 2 and z is 0, 1 or 2 provided that y and Z are not together greater than 2;
T ₁ is —N— or —CH—;
R _1a and R _1b are independently alkyl, substituted alkyl, halogen, cyano, nitro, OR ₁₀ , NR ₁₀ R ₁₁ , C (═O) R ₁₀ , CO ₂ R ₁₀ , C (═O) NR ₁₀ R ₁₁ , NR ₁₀ C (═O) R ₁₁ , NR ₁₀ C (═O) OR ₁₁ , SR ₁₀ , S (O) _o R _10a , NR ₁₀ SO ₂ R _10a , NHCH (alkyl) CO ₂ R ₁₀ , SO ₂ NR ₁₀ R _11, selected from cycloalkyl, heterocyclo, aryl, or heteroaryl;
Two R _1b together with each other or one R _1b together with R _1a to form a fused benzo ring;
R ₂ is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heterocyclo, or heteroaryl;
R _4a , R _4b and R _4c are selected from halogen, alkyl, cyano, haloalkyl, haloalkoxy, aryloxy, arylthio, or nitro;
R _9a and R _9b are each independently selected from hydrogen, halogen, C _1-4 alkyl, hydroxy, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, or cyano; or ,
R _9a and R _9b together form a keto (═O);
R _9c is selected from hydrogen or A ₁ -QA ₂ -R ₁₆ ;
A ₁ is a bond, C _1-2 alkylene, or C _2-3 alkenylene;
Q is a bond, —C (═O) —, —C (═O) NR ₁₇ —, —SO ₂ —, —CO ₂ —, or —NR ₁₇ CO ₂ —;
A ₂ is a _{bond, C 1 to 3 alkylene, C 2 to 3 alkenylene, -C 1 to 4} alkylene _-NR 17 _-, - _C 1~4 alkylene _{-NR 17 C (= O) -} , - C 1~4 alkylene -S -, _{- C 1-4} alkylene -SO ₂ -, or _-C a _1-4 alkylene -O-, wherein _{a 2} alkylene group is a branched or straight chain, optionally _CO 2 H, - Substituted with a group selected from CO ₂ (C _1-4 alkyl), —S (C _1-4 alkyl), NH ₂ , —NH (C _1-4 alkyl), or —N (C _1-4 alkyl) ₂ Is;
R ₁₀ and R ₁₁ are (i) independently of one another selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo; or (ii) R ₁₀ is taken together with R ₁₂ Forming a heteroaryl or heterocyclo;
R _10a is alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo;
R ₁₆ is selected from alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, or heterocyclo, each R ₁₆ optionally substituted with 1 to 3 R ₁₈ ;
R ₁₇ is hydrogen or alkyl;
R ₁₈ is C _1-6 alkyl, substituted C _1-6 alkyl, halogen, cyano, nitro, OR ₂₀ , NR ₂₀ R ₂₁ , C (═O) R ₂₀ , CO ₂ R ₂₀ , C (═O) NR. _{20 R 21, C (= O} ) NR 20 SO 2 R 20a, NR 20 C (= O) R 21, NR 20 C (= O) OR 21, SR 20, S (O) u R 20a, NR 20 SO ₂ R _20a, NHCH _{(alkyl) CO 2 R 20, NH- (} CH 2) 1~4 -CO 2 R 20, SO 2 NR 20 R 21, C 3~7 cycloalkyl, phenyl, 4-7 membered heterocyclo Or a C _3-7 cycloalkyl group, a phenyl group, a 4-7 membered heterocyclo group, or a 5 or 6 membered heteroaryl group is optionally selected from 1 to 2 R Substituted with ₂₂ ;
R ₂₀ and R ₂₁ are selected from hydrogen, alkyl, alkenyl, C _3-7 cycloalkyl, phenyl, benzyl, phenylethyl, naphthyl, 4-7 membered heterocyclo, or 5 or 6 membered heteroaryl, or When combined with the same nitrogen atom, they together form a heterocyclo or heteroaryl, wherein R ₂₀ and R ₂₁ are each optionally substituted with 1 to 2 R ₂₂ ;
R _20a is from alkyl, alkenyl, CO ₂ H, CO ₂ (alkyl), C _3-7 cycloalkyl, phenyl, benzyl, phenylethyl, naphthyl, 4-7 membered heterocyclo, or 5 or 6 membered heteroaryl. Each R _20a is optionally substituted with 1 to 2 R ₂₂ ;
R ₂₂ is (C _1-6 ) alkyl, (C _2-6 ) alkenyl, hydroxy, cyano, CF ₃ , O (C _1-6 alkyl), OCF ₃ , C (═O) H, C (═O ) (C _1-6 alkyl), CO ₂ H, CO ₂ (C _1-6 alkyl), NHCO ₂ (C _1-6 alkyl), —S (C _1-6 alkyl), —NH ₂ , NH (C _1-6 alkyl), N (C _1-6 alkyl) ₂ , N (CH ₃ ) ₃ ⁺ , SO ₂ (C _1-6 alkyl), C (═O) (C _1-4 alkylene) NH ₂ , C Selected from the group consisting of (═O) (C _1-4 alkylene) NH (alkyl) and C (═O) (C _1-4 alkylene) N (C _1-4 alkyl) ₂ ;
o and u are independently 1 or 2, and
n is 0, 1 or 2]
Or a pharmaceutically acceptable salt, hydrate or enantiomer thereof. 16. A compound according to claim 15, or a pharmaceutically acceptable salt, hydrate or enantiomer thereof, wherein R _{< 4a>} and R _<4c> are chloro. 16. A compound according to claim 15, or a pharmaceutically acceptable salt, hydrate or enantiomer thereof, wherein R _1a is cyano or halogen. formula:

16. A compound according to claim 15 or a pharmaceutically acceptable salt, hydrate or enantiomer thereof. R ₂ is selected from hydrogen, C _1-6 alkyl, or substituted C _1-6 alkyl, wherein the substituent is amino, NH (C _1-4 alkyl), N (alkyl) ₂ , C ( ═O) H, C (═O) C _1-4 alkyl, CO ₂ H, CO ₂ (C _1-4 alkyl), SO ₂ C _1-4 alkyl, SO ₃ H, and / or PO (OH) ₂ Is;
R _4a and R _4b are selected from halogen, C _1-4 alkyl, cyano, halo C _1-4 alkyl, or halo C _1-4 alkoxy;
J is — (CHR _9c ) _x —, or — (CH ₂ ) _y —NR _9c —;
R _9c is A ₁ -QA ₂ -R ₁₆ ;
R ₁₆ is, (a) hydrogen or optionally 1 to 2 substituents (said _{substituents,} OH, _{O (C} 1~4 _{alkyl),, - CO 2 H,} -CO 2 (C 1~4 alkyl) C _1-6 alkyl or C _2-6 alkenyl substituted with NH ₂ , —NH (C _1-4 alkyl), and / or N (C _1-4 alkyl) ₂ ; or
(B) furanyl, indolyl, carbazolyl, pyrazolyl, pyrrolyl, thienyl, pyridyl, pyrimidinyl, benzofuranyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, phenyl, piperidyl, pyrrolidinyl, pyridazinyl, C _3-7 cycloalkyl, piperazinyl, thiazolyl, morpholinyl, Selected from 1,2,5,6-tetrahydropyridyl, quinoxalinyl, benzothiazolyl, benzotriazolyl, benzodioxanyl, benzooxadiazolyl, thienopyrazolyl, tetrahydroquinolinyl, or quinolinyl,
Each cyclic R ₁₆ group is optionally substituted with up to 3 R ₁₈ ;
R ₁₇ is hydrogen or alkyl; and
R ₁₈ is hydrogen, (C _1-6 ) alkyl, (C _2-6 ) alkenyl, CO ₂ H, CO ₂ (C _1-6 alkyl), C (═O) H, C (═O) (C _1-6 alkyl), halogen, cyano, hydroxy, _{(C 1 to 4)} alkoxy, _{(C 1 to 4)} haloalkyl, _{(C 1 to 4) haloalkoxy, NH} 2, _{NH (C} 1~4 alkyl), N _{(C 1 to 4 alkyl) 2,} N _(C 1~4 ^{_{alkyl) 3 +, -C (= O}} ) (CH 2) NH 2, -NHCO 2 (C 1~4 _alkyl), SO _{2 (C} 1~ ₄ alkyl), phenyl, C _3-7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclo, wherein each R ₁₈ group is optionally substituted with 1-2 substituents (the substituted groups, _{(C 1 to 4)} alkyl, _{(C 2 to 4) alkenyl, CO 2 H, CO 2 (} C 1~4 alkyl), C (= O) H , C ( O) _{(C 1 to 4} alkyl), halogen, cyano, hydroxy, _{(C 1 to 4)} alkoxy, trifluoromethyl, _{trifluoromethoxy, NH} 2, _{NH (C} 1~4 alkyl), N _{(C 1 to 4} Alkyl) ₂ , N (C _1-4 alkyl) ₃ ⁺ , —C (═O) (CH ₂ ) NH ₂ , —NHCO ₂ (C _1-4 alkyl), and / or SO ₂ (C _1-4 alkyl). ) Is replaced with
19. A compound according to claim 18, or a pharmaceutically acceptable salt, hydrate or enantiomer thereof. formula:

[Where:
R _1a is cyano or halogen;
R _1b is halogen, C _1-4 alkyl, cyano, nitro, —CO ₂ H, —C (═O) H, —CO ₂ alkyl, or —C (═O) alkyl;
R ₂ is _{hydrogen, C 1-6} alkyl, or there _{C 1 to 6} alkyl substituted with CO ₂ H or CO _{2 (C 1 to 4} alkyl);
R ₁₈ is (C _1-4 ) alkyl, CO ₂ H, CO ₂ (C _1-4 alkyl), C (═O) H, C (═O) (C _1-4 alkyl), halogen, cyano, hydroxy, _{(C 1 to 4)} alkoxy, _{(C 1 to 4)} haloalkyl, _{(C 1 to 4) haloalkoxy, NH} 2, _{NH (C} 1~4 _alkyl), N _(C 1~4 _alkyl) 2, N (C _1-4 alkyl) ₃ ⁺ , —C (═O) (CH ₂ ) NH ₂ , —NHCO ₂ (C _1-4 alkyl), —C (═O) NHSO ₂ (C _1-4 alkyl), Selected from SO ₂ (C _1-4 alkyl), thienyl, tetrazolyl, triazolyl, pyrazolyl, or imidazolyl;
f is 0, 1, 2 or 3; and
n is 0 or 1]
21. A compound according to claim 19, or a pharmaceutically acceptable salt, hydrate or enantiomer thereof. formula:

[Where:
R _1a is halogen, cyano, nitro, trifluoromethyl, OCF ₃ , aryl, or heteroaryl;
R _1b is halogen, C _1-4 alkyl, cyano, nitro, —CO ₂ H, —C (═O) H, —CO ₂ alkyl, or —C (═O) alkyl;
R ₂ is _{hydrogen, C 1-6} alkyl, or there _{C 1 to 6} alkyl substituted with CO ₂ H or CO _{2 (C 1 to 4} alkyl);
R ₁₈ is (C _1-4 ) alkyl, CO ₂ H, CO ₂ (C _1-4 alkyl), C (═O) H, C (═O) (C _1-4 alkyl), halogen, cyano, hydroxy, _{(C 1 to 4)} alkoxy, _{(C 1 to 4)} haloalkyl, _{(C 1 to 4) haloalkoxy, NH} 2, _{NH (C} 1~4 _alkyl), N _(C 1~4 _alkyl) 2, N (C _1-4 alkyl) ₃ ⁺ , —C (═O) (CH ₂ ) NH ₂ , —NHCO ₂ (C _1-4 alkyl), —C (═O) NHSO ₂ (C _1-4 alkyl), Selected from SO ₂ (C _1-4 alkyl), thienyl, tetrazolyl, triazolyl, pyrazolyl, or imidazolyl;
f is 0, 1, 2 or 3; and
n is 0 or 1]
21. A compound according to claim 19, or a pharmaceutically acceptable salt, hydrate or enantiomer thereof. formula:

An intermediate useful for the preparation of a compound according to claim 1 selected from one of the following: R ₉ is

Chosen from;
A ₁ is a bond, C _1-2 alkylene, or C _2-3 alkenylene;
Q is a bond, —C (═O) —, —C (═O) NR ₁₇ —, —SO ₂ —, —CO ₂ —, or NR ₁₇ CO ₂ —;
A ₂ is a _{bond, C 1 to 3 alkylene, C 2 to 3 alkenylene, -C 1 to 4} alkylene _-NR 17 _-, - _C 1~4 alkylene _{-NR 17 C (= O) -} , - C 1~4 Alkylene-S—, —C _1-4 alkylene-SO ₂ —, or —C _1-4 alkylene-O—, wherein the A ₂ alkylene group is branched or straight chain, and CO ₂ H, —CO ₂ (C _1-4 alkyl), —S (C _1-4 alkyl), NH ₂ , —NH (C _1-4 alkyl), or —N (C _1-4 alkyl) _{2 as} appropriate. Substituted with a group selected from:
R ₁₇ is hydrogen or alkyl;
R ₁₈ and R ₁₉ are hydrogen, (C _1-6 ) alkyl, (C _2-6 ) alkenyl, CO ₂ H, CO ₂ (C _1-6 alkyl), C (═O) H, C (═O ) _{(C 1 to 6} alkyl), halogen, cyano, hydroxy, _{(C 1 to 4)} alkoxy, _{(C 1 to 4)} haloalkyl, _{(C 1 to 4) haloalkoxy, NH} 2, _{NH (C} 1~4 alkyl ), N (C _1-4 alkyl) ₂ , N (C _1-4 alkyl) ₃ ⁺ , —C (═O) (CH ₂ ) NH ₂ , —NHCO ₂ (C _1-4 alkyl), —C ( ═O) selected from NHSO ₂ (C _1-4 alkyl), SO ₂ (C _1-4 alkyl), phenyl, C _3-7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclo. Where R ₁₈ and R ₁₉ are each suitably 1 or 2 (C _1-4 ) alkyl, (C _2-4 ) alkenyl. , CO ₂ H, CO ₂ (C _1-4 alkyl), C (═O) H, C (═O) (C _1-4 alkyl), halogen, cyano, hydroxy, (C _1-4 ) alkoxy, tri fluoromethyl, _{trifluoromethoxy, NH} 2, _{NH (C} 1~4 alkyl), N _{(C 1 to 4 alkyl) 2,} N _{(C 1~4 ^{alkyl) 3 +, -C (= O}} ) (CH 2) NH _2, substituted by -NHCO _{2 (C 1 to 4} alkyl), and / or SO _{2 (C 1 to 4} alkyl);
f is 0, 1, 2, or 3; and
g is -1, 0, 1, or 2.
9. A compound according to claim 8, or a pharmaceutically acceptable salt, hydrate, salt, hydrate or enantiomer thereof. formula:

21. A compound according to claim 20, or an enantiomer, diastereomer, pharmaceutically acceptable salt, hydrate or solvate thereof. formula:

17. A compound according to claim 16 or an enantiomer, diastereomer, pharmaceutically acceptable salt, hydrate or solvate thereof.